ORCID Profile
0000-0001-8065-8838
Current Organisations
Garvan Institute of Medical Research
,
University of New South Wales
,
Saint Vincent's Hospital Sydney
,
Royal Australasian College of Physicians
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Publisher: MDPI AG
Date: 03-11-2021
Abstract: Monoclonal antibodies including trastuzumab, pertuzumab, and antibody-drug conjugates, form the backbone of HER2-positive breast cancer therapy. Unfortunately, an important adverse effect of these agents is cardiotoxicity, occurring in approximately 10% of patients. There is increasing published data regarding prevention strategies for cardiotoxicity, though seldom used in clinical practice. We performed a systematic review and meta-analysis of randomized-controlled trials to evaluate pharmacotherapy for the prevention of monoclonal HER2-directed antibody-induced cardiotoxicity in patients with breast cancer. Online databases were queried from their inception until October 2021. Effects were determined by calculating risk ratios (RRs) and 95% confidence intervals (CI) or mean differences (MD) using random-effects models. We identified five eligible trials. In the three trials (n = 952) reporting data on the primary outcome of cardiotoxicity, there was no clear effect for patients assigned active treatment compared to control (RR = 0.90, 95% CI 0.63 to 1.29, p = 0.57). Effects were similar for ACE-I/ARB and beta-blockers (p homogeneity = 0.50). Active treatment reduced the risk of HER2 therapy interruptions (RR = 0.57, 95% CI 0.43 to 0.77, p 0.001) with similar findings for ACE-I/ARB and beta-blockers (p homogeneity = 0.97). Prophylactic treatment with ACE-I/ARB or beta-blocker therapy may be of value for cardio-protection in patients with breast cancer prescribed monoclonal antibodies. Further, adequately powered randomized trials are required to define the role of routine prophylactic treatment in this patient group.
Publisher: Wiley
Date: 16-01-2007
DOI: 10.1111/J.1445-5994.2007.01246.X
Abstract: We prospectively assessed 100 consecutive inpatient referrals made to the Medical Oncology Unit. The major end-point was the time to diagnostic biopsy. Referral trends and treatment outcomes were also recorded. Our results show that the referring units undertook the diagnostic process in the vast majority and the time to inpatient diagnostic biopsy has fallen from 10 to 4.6 days, compared with a similar study 13 years ago. This emphasizes the changing role of the oncologist in current day multidisciplinary cancer care.
Publisher: Springer New York
Date: 09-09-2014
Publisher: Elsevier BV
Date: 03-2017
Publisher: Wiley
Date: 26-11-2020
DOI: 10.1111/ANS.15487
Abstract: Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2015
DOI: 10.1158/1538-7445.SABCS14-P3-05-14
Abstract: Background ER+ breast cancers are predominantly p53 wildtype (wt). Despite this genotype, these cancers are relatively resistant to chemotherapy-induced apoptosis in the presence of estrogen. Thus, current clinical practice is to administer hormonal therapy and chemotherapy sequentially rather than concurrently. Using the ER+ 53wt cell line MCF-7, we previously demonstrated that ER bound by either the ER agonist estradiol or partial antagonist tamoxifen inhibits the expression of a set of proapoptotic p53 target genes, whereas the full ER antagonist fulvestrant, a selective ER downregulator (SERD), removes the ER-mediated suppression of these genes, sensitizing breast cancer cells to p53-mediated cell death .We hypothesize that effective chemoendocrine therapy requires complete ER antagonism resulting in ER downregulation, increased p53 activity, and ultimately apoptosis. Methods: To model mechanisms of tumor sensitivity and resistance to therapy in vivo, therapeutic experiments were performed in immunodeficient mice bearing ER+ 53wt tumor xenografts derived from a 61-year-old African-American female with grade 2 invasive ductal carcinoma. The mice were randomly assigned to the following treatment groups: A) fulvestrant B) tamoxifen, C) doxorubicin, D) fulvestrant plus doxorubicin, E) tamoxifen plus doxorubicin, and F) control. Tumors were measured weekly for 42 days to determine treatment effects on growth. In addition, RNA was harvested from tumors at an early time point for RNA sequencing to determine genes regulated by the treatments. Results: Combination therapy comprising doxorubicin plus fulvestrant resulted in tumor regression compared with single-agent or doxorubicin plus tamoxifen treatment, which inhibited the growth of tumors but did not lead to their regression. Conclusions: Current paradigms for the treatment of ER+ breast cancer either in the adjuvant or advanced setting have involved the sequential use of endocrine therapy and chemotherapy. This protocol is partially based on evidence of potential antagonism between tamoxifen and chemotherapy as observed in early studies. Our published work in vitro and the preclinical study presented here suggest that complete ER antagonism with SERDs such as fulvestrant is required to overcome the ability of ER to block p53-mediated apoptosis. Our results suggest treatments involving fulvestrant concurrent with chemotherapies involving p53 activation should be considered for the treatment of patients with ER+ 53wt breast cancer. Citation Format: Shiliang A Cao, Elgene Lim, Myles Brown, Shannon T Bailey. Modeling chemoendocrine therapy for ER+ 53wt luminal breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2015 (9 Suppl):Abstract nr P3-05-14.
Publisher: Wiley
Date: 06-11-2016
DOI: 10.1111/AJCO.12783
Abstract: To evaluate the attitudes of patients with different cancers towards research biopsies outside a clinical trial. Patients with metastatic cancer completed a questionnaire that assessed patients' willingness to consider research biopsies. Research biopsies were ided into two groups: biopsies performed as stand-alone procedures (research purposes only biopsy, RPOB) or performed during a clinically indicated biopsy (additional pass biopsy, APB). Factors analyzed included biopsy timing, biopsy site, sociodemographic information and information about prior trial participation. Univariate and multivariable analyses were conducted using random-effects logistic regression. One hundred and sixty-five patients with cancer (40 melanoma, 37 colorectal, 32 breast, 30 lung, 26 prostate) completed the questionnaire. Patients with melanoma demonstrated the greatest willingness to consider a research biopsy compared to patients with other cancer types (P < 0.05). Patients' ethnicity, time since previous biopsies, time since metastatic diagnosis, and previous trial enrolment were all statistically significant for willingness to consider a research biopsy on univariate analysis. When adjusting for statistically significant variables on univariate analysis, the odds of patients considering APBs were 14.6 times greater than RPOBs (P < 0.0001). Patients were also more willing to consider having blood or skin taken for research purposes (P < 0.0001) compared to liver and bone biopsies. Patients with cancer show a greater willingness to consider APBs compared to RPOBs, and biopsies performed at less invasive body sites. There are differences in the attitudes of patients with different cancers towards research biopsies. Further research addressing motivations and barriers to research biopsies should be considered to increase the availability of this important resource.
Publisher: MDPI AG
Date: 12-02-2022
Abstract: Endocrine therapy forms the backbone of systemic therapy for the majority of persons with early and late-stage breast cancer. However, the side effects can negatively affect quality of life, and impact treatment adherence and overall oncological outcomes. Adverse effects on cognition are common, underreported and challenging to manage. We aim to describe the nature, incidence, risk factors and underlying mechanisms of endocrine therapy-induced cognitive dysfunction. We conducted a comprehensive literature review of the studies reporting on cognitive dysfunction associated with endocrine therapies for breast cancer. We also summarise prevention and treatment strategies, and ongoing research. Given that patients are taking endocrine therapies for longer durations than ever before, it is essential that these side effects are managed pro-actively within a multi-disciplinary team in order to promote adherence to endocrine therapy and improve patients' quality of life.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2019
DOI: 10.1007/S10549-018-5054-X
Abstract: Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups. This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS. Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441 ribociclib, [46.4%] palbociclib, [30.8%] or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56 95% CI 0.50-0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29-0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54-0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity. Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2018
DOI: 10.1038/S41467-018-04619-5
Abstract: Understanding the dynamics of endogenous protein–protein interactions in complex networks is pivotal in deciphering disease mechanisms. To enable the in-depth analysis of protein interactions in chromatin-associated protein complexes, we have previously developed a method termed RIME (Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins). Here, we present a quantitative multiplexed method (qPLEX-RIME), which integrates RIME with isobaric labelling and tribrid mass spectrometry for the study of protein interactome dynamics in a quantitative fashion with increased sensitivity. Using the qPLEX-RIME method, we delineate the temporal changes of the Estrogen Receptor alpha (ERα) interactome in breast cancer cells treated with 4-hydroxytamoxifen. Furthermore, we identify endogenous ERα-associated proteins in human Patient-Derived Xenograft tumours and in primary human breast cancer clinical tissue. Our results demonstrate that the combination of RIME with isobaric labelling offers a powerful tool for the in-depth and quantitative characterisation of protein interactome dynamics, which is applicable to clinical s les.
Publisher: Bioscientifica
Date: 2019
DOI: 10.1530/ERC-18-0317
Abstract: Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2014
Publisher: Bioscientifica
Date: 12-2016
DOI: 10.1530/ERC-16-0427
Abstract: The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to ‘push’ ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2013
DOI: 10.1158/1538-7445.AM2013-1788
Abstract: Background: Triple Negative Breast Cancer (TNBC) comprises 15% of all breast cancers, and has a poor prognosis relative to other breast cancer subtypes. Inhibition of poly (ADP-ribose) polymerase (PARP) causes the degeneration of single-strand DNA breaks to more lethal double-strand breaks (DSBs), and also traps PARP-DNA complexes, which must be repaired or bypassed by homologous recombination (HR). BRCA1 plays a critical role in HR and its activity is in part regulated by cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation. PARP inhibition results in synthetic lethality in cells that have impaired HR, such as BRCA-deficient cells. Other CDK family members activate additional components of the HR pathway. Here, we show that HR-proficient TNBC cells can be sensitized to PARP inhibition through use of CDK inhibition to impair BRCA1 function and disrupt HR. Methods: We examined the effects of dinaciclib (CDK1, 2, 5 and 9 inhibitor), γ-irradiation and veliparib (PARP inhibitor) on a panel of BRCA1 wild type TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549). Levels of phospho-S1497 BRCA1 (pBRCA1 CDK phosphorylation site), γ-H2AX, and RAD51 were measured by western blot to assess effects on HR proteins. A direct assessment of DSB repair was measured using the U2OS-DR-GFP reporter system. Cell viability was measured using Cell-Titer Glo assays. Patient-derived TNBC xenograft models were established in immunocompromised NOD-SCID-IL2γ-/- mice, and implanted orthotopically into cohorts of mice for in vivo efficacy studies. Results: There was a significant reduction in total and pBRCA1 and RAD51 protein levels with increasing concentrations of dinaciclib in all TNBC cell lines. In response to 10 Gy γ-irradiation treatment, pretreatment with dinaciclib (20 nM) reduced the percentage of cells with greater than five BRCA1 foci from 54% to 5% (P & 0.001) and the percentage of cells with greater than 5 RAD51 foci from 26% to 4% (P = 0.001). In U2OS-DR-GFP assays, expression of GFP was detected in 3.4% of the vehicle group and in 1.9% of dinaciclib treated cells. Cell viability assays following five days of dinaciclib, veliparib or the combination revealed in vitro cytotoxic synergy in all three TNBC cell lines. In an orthotopic TNBC model derived from a primary patient s le, the relative tumor volumes over a 30-day treatment period for vehicle, dinaciclib, veliparib and combination- treated mice were 5.6-fold, 3.3-fold, 3.2-fold and 0.66-fold (P & 0.001) that of the initial tumor volume at the start of treatment. Tumor volume decreased only in the combination arm. Conclusion: CDK inhibition effectively inhibits HR, and renders BRCA-proficient TNBC cells sensitive to PARP inhibition. This combination represents an effective strategy for the treatment of TNBC. Citation Format: Shawn F. Johnson, Neil Johnson, David Chi, Benjamin Primack, Alan D. D'Andrea, Elgene Lim, Geoffrey I. Shapiro. The CDK inhibitor dinaciclib sensitizes triple-negative breast cancer cells to PARP inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research 2013 Apr 6-10 Washington, DC. Philadelphia (PA): AACR Cancer Res 2013 (8 Suppl):Abstract nr 1788. doi:10.1158/1538-7445.AM2013-1788
Publisher: MDPI AG
Date: 04-02-2019
DOI: 10.3390/IJMS20030667
Abstract: Basal-like breast cancer (BLBC) is an aggressive molecular subtype that represents up to 15% of breast cancers. It occurs in younger patients, and typically shows rapid development of locoregional and distant metastasis, resulting in a relatively high mortality rate. Its defining features are that it is positive for basal cytokeratins and, epidermal growth factor receptor and/or c-Kit. Problematically, it is typically negative for the estrogen receptor and human epidermal growth factor receptor 2 (HER2), which means that it is unsuitable for either hormone therapy or targeted HER2 therapy. As a result, there are few therapeutic options for BLBC, and a major priority is to define molecular subgroups of BLBC that could be targeted therapeutically. In this review, we focus on the highly proliferative and anti-apoptotic phenotype of BLBC with the goal of defining potential therapeutic avenues, which could take advantage of these aspects of tumor development.
Publisher: Frontiers Media SA
Date: 27-01-2016
Publisher: Wiley
Date: 10-2018
DOI: 10.1111/AJCO.13064
Abstract: Resistance to endocrine therapy is a significant therapeutic challenge in the treatment of women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy have been shown to improve progression free survival, overall response rate and clinical benefit rate in women with HR+ HER2- metastatic breast cancer compared with endocrine therapy alone. This review examines the clinical evidence to support the use of CDK4/6 inhibitors in first and second line settings. Practical guidance is provided for the use of CDK4/6 inhibitors, including tolerability data, monitoring requirements and management of key toxicities for each of the available agents.
Publisher: Informa UK Limited
Date: 12-2012
DOI: 10.1128/MCB.00468-12
Publisher: Elsevier BV
Date: 06-2013
Publisher: Wiley
Date: 11-2020
DOI: 10.1111/AJCO.13461
Publisher: Wiley
Date: 10-2018
DOI: 10.1111/AJCO.13065
Abstract: Cyclin-dependent kinase (CDK4/6) inhibitors in combination with endocrine therapy are currently the optimal first line treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) non- lified metastatic breast cancer (MBC). However, not all patients benefit from this treatment and all patients will inevitably progress. Identifying therapeutic strategies in this setting is therefore of immediate clinical importance. We present an overview of the mechanisms of resistance to CDK4/6 inhibitors and review potential biomarkers that may guide therapy selection. We also discuss the use of CDK4/6 inhibitors in the context of non-HR-positive/HER2-non- lified breast cancer and in combination with therapies other than endocrine therapy.
Publisher: eLife Sciences Publications, Ltd
Date: 20-05-2014
DOI: 10.7554/ELIFE.01763
Abstract: Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. In this study, we report the identification of MELK as a novel oncogenic kinase from an in vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library. Analysis of clinical data reveals a high level of MELK overexpression in BBC, a feature that is largely dependent on FoxM1, a master mitotic transcription factor that is also found to be highly overexpressed in BBC. Ablation of MELK selectively impairs proliferation of basal-like, but not luminal breast cancer cells both in vitro and in vivo. Mechanistically, depletion of MELK in BBC cells induces caspase-dependent cell death, preceded by defective mitosis. Finally, we find that Melk is not required for mouse development and physiology. Together, these data indicate that MELK is a normally non-essential kinase, but is critical for BBC and thus represents a promising selective therapeutic target for the most aggressive subtype of breast cancer.
Publisher: Frontiers Media SA
Date: 23-06-2021
Abstract: Taxane-based chemotherapy regimens are in widespread use as standard of care treatment for patients with early breast cancer, though rarely its use can be complicated by taxane-induced pneumonitis (TIP). While breast cancer is the most diagnosed cancer in women worldwide, TIP remains under-described in this setting. Key questions relate to its incidence, diagnosis and management, potential predictive biomarkers, and the balance between this life-threatening toxicity and curatively intended treatment. At a single Australian institution, 6 cases of TIP are identified among 132 patients treated with a paclitaxel-containing regimen for early breast cancer (4.55%, 95% confidence interval 1.69-9.63%). This review first outlines the presentation, management, and outcomes for these cases, then answers these questions and proposes an approach to suspected TIP in patients with breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 22-11-2016
DOI: 10.1007/S10555-016-9648-7
Abstract: Carcinoma cells that are induced to suppress their epithelial features and upregulate mesenchymal gene expression programs acquire traits that promote an invasive and metastatic phenotype. This is achieved through the expression of a program termed the epithelial-to-mesenchymal transition (EMT)-a fundamental cell-biological process that plays key roles in embryogenesis and wound healing. Re-activation of the EMT during cancer promotes disease progression and enhances the metastatic phenotype by bestowing upon previously benign carcinoma cell traits such as migration, invasion, resistance to anoikis, chemoresistance and tumour-initiating potential. Herein, we discuss recent insights into the function of the EMT and cancer cell plasticity during cancer progression, with a focus on their role in promoting successful completion of the later stages of the metastatic cascade.
Publisher: Elsevier BV
Date: 10-2011
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.DRUDIS.2019.12.001
Abstract: Cyclin-dependent kinase 2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in a range of biological processes. CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation. CDK2 and its regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features. Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1007/S10549-021-06456-5
Abstract: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.CELREP.2021.109722
Abstract: DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation.
Publisher: MDPI AG
Date: 03-10-2021
Abstract: The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.
Publisher: MDPI AG
Date: 16-05-2019
Abstract: Tumor antigens are responsible for initiating an immune response in cancer patients, and their identification may provide new biomarkers for cancer diagnosis and targets for immunotherapy. The general use of serum antibodies to identify tumor antigens has several drawbacks, including dilution, complex formation, and background reactivity. In this study, antibodies were generated from antibody-secreting cells (ASC) present in tumor-draining lymph nodes of 20 breast cancer patients (ASC-probes) and were used to screen breast cancer cell lines and protein microarrays. Half of the ASC-probes reacted strongly against extracts of the MCF-7 breast cancer cell line, but each with a distinct antigen recognition profile. Three of the positive ASC-probes reacted differentially with recombinant antigens on a microarray containing cancer-related proteins. The results of this study show that lymph node-derived ASC-probes provide a highly specific source of tumor-specific antibodies. Each breast cancer patient reacts with a different antibody profile which indicates that targeted immunotherapies may need to be personalized for in idual patients. Focused microarrays in combination with ASC-probes may be useful in providing immune profiles and identifying tumor antigens of in idual cancer patients.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2014
DOI: 10.1038/NATURE13119
Publisher: Wiley
Date: 09-2021
DOI: 10.1111/AJCO.13655
Abstract: Advances in human epidermal growth factor receptor 2 (HER2)‐directed therapies have revolutionised the care of patients with HER2‐positive breast cancer. While adjuvant trastuzumab in combination with chemotherapy has dramatically improved the prognosis for patients with early‐stage disease, up to a quarter of patients will develop recurrent disease. The standard‐of‐care treatment paradigm has evolved with the introduction of newer HER2‐directed therapies and increasing use of neoadjuvant systemic therapy, the latter providing us with important functional data to HER2‐directed therapies and impacting subsequent adjuvant therapy decisions. However, these new strategies come at a cost of increased toxicity and economic burden, and only a subset of patients benefit from such approaches. Thus, ongoing work is required to identify predictive biomarkers of response, to de‐escalate treatment in patients who may do just as well with less therapy, and new therapeutic approaches for patients who do not respond to currently used therapies. In this review, we will examine the current therapeutic landscape, summarise the latest evidence, and list the current treatment algorithms for early stage HER2‐positive breast cancer.
Publisher: Research Square Platform LLC
Date: 09-2020
DOI: 10.21203/RS.3.RS-62718/V1
Abstract: Antagonistic sex hormone activity occurs in mammary gland development, whereby estrogen stimulates and androgen inhibits post-pubertal growth, but the mechanistic basis of this is largely unknown. Whether sex hormone antagonism occurs in the context of breast cancer is also unclear. The estrogen receptor alpha (ER) unequivocally drives the majority of breast malignancies, but the role of the androgen receptor (AR) is controversial, particularly in the context of ER-positive (ER+) tumours resistant to standard-of-care ER targeting therapies. The controversy has constrained clinical implementation of new drugs that influence AR activity for treatment of this disease. Using a erse panel of cell line and patient-derived models of ER+ breast cancer, we demonstrate that activation, not suppression, of AR activity exerts potent anti-tumour activity in multiple clinically relevant contexts, including tumours resistant to ER targeting therapy. We also show that AR agonists can be combined with old and new (i.e. Palbociclib, a CDK4/6 inhibitor) standard-of-care agents to enhance therapeutic efficacy. Mechanistically, agonist activation of AR altered the distribution of ER and its coactivators (p300, SRC-3) on chromatin, resulting in repression of ER-regulated cell cycle genes and up-regulation of AR target genes, including known tumour suppressors. Consistent with the mechanistic findings, a gene signature of AR activity derived from in vivo models positively predicted disease survival in multiple large, well-annotated clinical cohorts of ER+ breast cancer, outperforming existing pan-cancer or breast cancer specific signatures. These findings provide compelling evidence that AR has a tumour suppressor role in ER+ breast cancer and resolves an important clinical controversy concerning the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
Publisher: Wiley
Date: 10-10-2007
DOI: 10.1111/J.1445-2197.2007.04287.X
Abstract: Liver metastases are a common event in colorectal carcinoma. Significant advances have been made in managing these patients in the last decade, including improvements in staging and surgical techniques, an increasing armamentarium of chemotherapeutics and multiple local ablative techniques. While combination chemotherapy significantly improves median patient survival, surgical resection provides the only prospect of cure and is the focus of this review. Interpretation of published work in this field is challenging, particularly as there is no consensus to what is resectable disease. Of particular interest recently has been the use of neoadjuvant treatment for downstaging and downsizing disease in patients with initially unresectable liver metastases, in the hope of response leading to potentially curative surgery. This review summarizes the recent developments and consensus guidelines in the areas of staging, chemotherapy, local ablative techniques, radiation therapy and surgery, emphasizing the multidisciplinary approach to this disease and ongoing controversies in this field and examines the changing paradigms in the management of colorectal hepatic metastases.
Publisher: Elsevier BV
Date: 07-2011
Publisher: Springer Science and Business Media LLC
Date: 22-09-2016
DOI: 10.1038/BJC.2016.303
Publisher: Bioscientifica
Date: 02-2019
DOI: 10.1530/ERC-18-0333
Abstract: The role of androgen receptor (AR) in endocrine-resistant breast cancer is controversial and clinical trials targeting AR with an AR antagonist (e.g., enzalutamide) have been initiated. Here, we investigated the consequence of AR antagonism using in vitro and in vivo models of endocrine resistance. AR antagonism in MCF7-derived tamoxifen-resistant (TamR) and long-term estrogen-deprived breast cancer cell lines were achieved using siRNA-mediated knockdown or pharmacological inhibition with enzalutamide. The efficacy of enzalutamide was further assessed in vivo in an estrogen-independent endocrine-resistant patient-derived xenograft (PDX) model. Knockdown of AR inhibited the growth of the endocrine-resistant cell line models. Microarray gene expression profiling of the TamR cells following AR knockdown revealed perturbations in proliferative signaling pathways upregulated in endocrine resistance. AR loss also increased some canonical ER signaling events and restored sensitivity of TamR cells to tamoxifen. In contrast, enzalutamide did not recapitulate the effect of AR knockdown in vitro , even though it inhibited canonical AR signaling, which suggests that it is the non-canonical AR activity that facilitated endocrine resistance. Enzalutamide had demonstrable efficacy in inhibiting AR activity in vivo but did not affect the growth of the endocrine-resistant PDX model. Our findings implicate non-canonical AR activity in facilitating an endocrine-resistant phenotype in breast cancer. Unlike canonical AR signaling which is inhibited by enzalutamide, non-canonical AR activity is not effectively antagonized by enzalutamide, and this has important implications in the design of future AR-targeted clinical trials in endocrine-resistant breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2021
Publisher: Springer Science and Business Media LLC
Date: 31-08-2021
DOI: 10.1038/S41523-021-00312-X
Abstract: Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 lification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/ BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2005
Publisher: Springer Science and Business Media LLC
Date: 26-03-2010
DOI: 10.1186/BCR2560
Publisher: Elsevier BV
Date: 09-2023
Publisher: Proceedings of the National Academy of Sciences
Date: 18-07-2012
Abstract: Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2–expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients with either ABT-737, docetaxel, or a combination. Tumor response and overall survival were significantly improved by combination therapy, but only for tumor xenografts that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitizes the tumor cells to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2. Notably, BH3 mimetics also appeared effective in BCL-2–expressing xenograft lines that harbored p53 mutations. Our findings provide in vivo evidence that BH3 mimetics can be used to sensitize primary breast tumors to chemotherapy and further suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer.
Publisher: MDPI AG
Date: 18-01-2022
Abstract: Epigenetic therapies remain a promising, but still not widely used, approach in the management of patients with cancer. To date, the efficacy and use of epigenetic therapies has been demonstrated primarily in the management of haematological malignancies, with limited supportive data in solid malignancies. The most studied epigenetic therapies in breast cancer are those that target DNA methylation and histone modification however, none have been approved for routine clinical use. The majority of pre-clinical and clinical studies have focused on triple negative breast cancer (TNBC) and hormone-receptor positive breast cancer. Even though the use of epigenetic therapies alone in the treatment of breast cancer has not shown significant clinical benefit, these therapies show most promise in use in combinations with other treatments. With improving technologies available to study the epigenetic landscape in cancer, novel epigenetic alterations are increasingly being identified as potential biomarkers of response to conventional and epigenetic therapies. In this review, we describe epigenetic targets and potential epigenetic biomarkers in breast cancer, with a focus on clinical trials of epigenetic therapies. We describe alterations to the epigenetic landscape in breast cancer and in treatment resistance, highlighting mechanisms and potential targets for epigenetic therapies. We provide an updated review on epigenetic therapies in the pre-clinical and clinical setting in breast cancer, with a focus on potential real-world applications. Finally, we report on the potential value of epigenetic biomarkers in diagnosis, prognosis and prediction of response to therapy, to guide and inform the clinical management of breast cancer patients.
Publisher: MDPI AG
Date: 17-02-2021
Abstract: Systemic treatment of hormone receptor-positive (HR+) breast cancer is undergoing a renaissance, with a number of targeted therapies including CDK4/6, mTOR, and PI3K inhibitors now approved for use in combination with endocrine therapies. The increased use of targeted therapies has changed the natural history of HR+ breast cancers, with the emergence of new escape mechanisms leading to the inevitable progression of disease in patients with advanced cancers. The identification of new predictive and pharmacodynamic biomarkers to current standard-of-care therapies and discovery of new therapies is an evolving and urgent clinical challenge in this setting. While traditional, routinely measured biomarkers such as estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) still represent the best prognostic and predictive biomarkers for HR+ breast cancer, a significant proportion of patients either do not respond to endocrine therapy or develop endocrine resistant disease. Genomic tests have emerged as a useful adjunct prognostication tool and guide the addition of chemotherapy to endocrine therapy. In the treatment-resistant setting, mutational profiling has been used to identify ESR1, PIK3CA, and AKT mutations as predictive molecular biomarkers to newer therapies. Additionally, pharmacodynamic biomarkers are being increasingly used and considered in the metastatic setting. In this review, we summarise the current state-of-the-art therapies prognostic, predictive, and pharmacodynamic molecular biomarkers and how these are impacted by emerging therapies for HR+ breast cancer.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1007/S11912-014-0427-8
Abstract: The androgen receptor (AR) is expressed in the majority of breast cancer and across the three main breast cancer subtypes. Historically, the oncogenic role of AR has best been described in molecular apocrine breast cancers, an estrogen receptor (ER)-/AR+ subtype which has a steroid response signature similar to that in the ER-positive breast cancer. The signalling effect of AR is likely to be different across breast cancer subtypes, and particularly important is its interaction with ER signalling. Despite the high frequency of AR expression in breast cancer, it is still not a standard clinical practice to use AR antagonists as therapy. Older trials of AR-directed therapies in breast cancer have had generally been disappointing. More recently, more potent, next-generation, AR-directed therapies have been developed in the context of prostate cancer. Here, we will review the emerging literature dissecting the role of AR signalling in a context-dependent manner in breast cancer and the renewed interest and wave of clinical trials targeting the AR in breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2020
DOI: 10.1186/S13058-020-01318-2
Abstract: Resistance to endocrine therapy is a major clinical challenge in the management of oestrogen receptor (ER)-positive breast cancer. In this setting, p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment-resistant ER-positive breast cancer. We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate anti-tumour effects in p53 wildtype and p53 mutant ER-positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and endocrine-resistant ER-positive breast cancer. We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model. We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes.
Publisher: Wiley
Date: 2021
DOI: 10.1111/AJCO.13555
Publisher: Springer Science and Business Media LLC
Date: 25-08-2021
DOI: 10.1038/S41467-021-25422-9
Abstract: CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.
Publisher: Wiley
Date: 25-10-2017
Abstract: With the advent of immunotherapies for cancer, there is growing interest in the identification of tumor antigens. Tumor antigens are self-molecules altered through e.g. genetic mutations (neoantigens), protein truncation, protein misfolding, or abnormal posttranslational modifications. To induce an immune response, tumor antigens need to be secreted into the tumor environment and presented to the immune system in the draining lymph nodes, resulting in the generation of tumor-specific effector cells and antibodies. Cytotoxic T cells are thought to be responsible for killing of tumor cells, and several recent studies have used MS, combined with exome/transcriptome sequencing and bioinformatics, to identify their cognate peptide ligands on tumor MHC class I molecules. Circulating (serum) antibodies have been more widely used to identify tumor antigens in a range of human cancers, using 2D Western blots, immunoaffinity, and microarray technologies. More specific antibody probes have been generated by harvesting antibodies directly from antibody-secreting cells through in vitro cultures of lymph node cells (antibody-secreting cells probes) or B-cell immortalization. Further identification and characterization of tumor antigens is likely to have important implications for cancer diagnostic and biomarker discovery, immune profiling, and the development of cancer vaccines and targeted immunotherapies.
Publisher: Elsevier BV
Date: 09-2013
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 08-2022
DOI: 10.1007/S10549-022-06690-5
Abstract: Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity. This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200 mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥ Grade 3), prolonged ( 7 days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported. Incidence of investigator assessed severe diarrhea (Grade ≥ 3) was 1.4% (1 patient in Arm 1). Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. No patient discontinued treatment due to diarrhea. Nine patients (12.7%) had a dose reduction, and 7 patients (9.9%) had a dose omission due to diarrhea. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms. The results suggest that diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications.
Publisher: Harborside Press, LLC
Date: 09-2013
Abstract: Breast cancer is a substantial contributor to adolescent and young adult (AYA) malignancies, defined as a diagnosis of cancer between the ages of 15 and 39. In the United States, 6.6% of breast cancer cases are diagnosed among women younger than 40 years. When breast cancer occurs in AYAs, it typically has a worse prognosis and more-aggressive phenotype higher proportions of high-grade and later-stage tumors lower estrogen receptor positivity and, in some studies, higher expression of HER2. Age-specific differences in the biology of AYA breast cancer have been explored in large-scale genomic studies with mixed results. Although some studies suggest that AYA breast cancer has a unique biology, others have shown that its aggressive nature is the result of higher frequencies of aggressive breast cancer subtypes among younger patients. More recently, stromal-related gene signatures have shown prognostic significance in AYA breast cancer, suggesting that differences in microenvironment may account for age-specific differences in breast cancer behavior. Although general principles for selecting cytotoxic and targeted agents are similar between AYAs and the general breast cancer population, endocrine therapy choices in the adjuvant and metastatic settings vary by pre- and postmenopausal status. The role of ovarian suppression remains controversial and is reviewed. The AYA population is a unique group of patients who need in idualized care, including considerations of hereditary breast cancer predispositions, future fertility, and the effect of therapy on immediate and long-term quality of life, all of which require coordinated multidisciplinary care. This article addresses the epidemiology, genetics, and management of breast cancer in AYA women and highlights unique medical issues important to this population.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2020
DOI: 10.1186/S13058-020-01306-6
Abstract: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical s les demonstrates that ID4 is lified and overexpressed at a higher frequency in BRCA1 -mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2013
DOI: 10.1158/1538-7445.AM2013-2313
Abstract: Background: The estrogen receptor (ER) is expressed in ≈70% of sporadic breast cancer and activates genes driving cell proliferation and tumorigenesis. We have previously performed genome-wide analysis of ER binding sites in MCF-7 breast cancer cells and identified distinct mechanisms of tumorigenic ER signaling. Using EpCAM and CD49f as markers to enrich for ER-positive (ER+) cells obtained from primary non-malignant breast tissue, we seek to elucidate differences in ER signaling between normal and primary and metastatic ER+ breast cancer cells. Methods: Viable breast epithelial cells were obtained from patients undergoing reduction mammoplasties, and ER+ breast cancer cells from primary tumors and metastatic effusions. Following dissociation into single cells, EpCAM+ cell subpopulations were isolated and stimulated with estradiol. Gene expression microarray analysis, chromatin immunoprecipitation and DNA sequencing (ChIP-seq) on transcription factors and histone modifications as well as DNAse I hypersensitivity assays (DHS) were performed, and compared to MCF-7 breast cancer cells. Results: Triplicates of normal, ER+ breast cancers, and metastatic ER+ cancer were analyzed. Gene expression profiles revealed differences in estradiol regulated genes between primary normal, breast tumor, and metastatic ER+ breast cancer cells. Genes that promote cell cycling and cell proliferation were downregulated in non-malignant tissue but were upregulated in breast cancer cells. Our ChIP-seq results showed differential binding of ER between normal and ER+ breast cancer with little common overlap, and motif analysis of these binding sites demonstrated the enrichment of ERE motifs in common sites, TCF12 motifs in unique normal sites, and FOXA1 motifs in unique breast cancer sites. Analyses of the distribution of histone modifications and DHS regions demonstrated distinct patterns at shared, normal, and breast cancer ER binding sites, suggesting functionality and further validating differential ER binding. Conclusions: There are contrasting differences in ER signaling between normal mammary and ER+ breast cancer cells, with estrogen appearing to have anti-proliferative effects in normal luminal cells compared to pro-proliferative effects in BC. ER ChIP-seq has identified unique motifs, distribution of histone modifications, and DHS regions specific to unique normal, cancer and shared ER binding sites. Our studies point to TCF12 as a potential ER pioneer cofactor in non-malignant breast tissue and provide more data in support of FOXA1 as an important ER coregulator in ER+ breast cancer. Our data provides evidence for key alterations in ER-signaling during tumorigenesis and could lead to the identification of novel strategies to target breast cancer specific ER signaling. Citation Format: David Chi, Housheng He, Tony Yeung, Rinath Jeselsohn, Stuart Schnitt, Judy Garber, Andrea Richardson, Elgene Lim, Myles Brown. Differences in estrogen receptor signaling in normal mammary epithelial cells and ER-positive primary breast tumors and metastases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research 2013 Apr 6-10 Washington, DC. Philadelphia (PA): AACR Cancer Res 2013 (8 Suppl):Abstract nr 2313. doi:10.1158/1538-7445.AM2013-2313
Publisher: Springer Science and Business Media LLC
Date: 24-02-2022
Publisher: Springer Science and Business Media LLC
Date: 10-05-2021
DOI: 10.1186/S13073-021-00885-Z
Abstract: High throughput single-cell RNA sequencing (scRNA-Seq) has emerged as a powerful tool for exploring cellular heterogeneity among complex human cancers. scRNA-Seq studies using fresh human surgical tissue are logistically difficult, preclude histopathological triage of s les, and limit the ability to perform batch processing. This hindrance can often introduce technical biases when integrating patient datasets and increase experimental costs. Although tissue preservation methods have been previously explored to address such issues, it is yet to be examined on complex human tissues, such as solid cancers and on high throughput scRNA-Seq platforms. Using the Chromium 10X platform, we sequenced a total of ~ 120,000 cells from fresh and cryopreserved replicates across three primary breast cancers, two primary prostate cancers and a cutaneous melanoma. We performed detailed analyses between cells from each condition to assess the effects of cryopreservation on cellular heterogeneity, cell quality, clustering and the identification of gene ontologies. In addition, we performed single-cell immunophenotyping using CITE-Seq on a single breast cancer s le cryopreserved as solid tissue fragments. Tumour heterogeneity identified from fresh tissues was largely conserved in cryopreserved replicates. We show that sequencing of single cells prepared from cryopreserved tissue fragments or from cryopreserved cell suspensions is comparable to sequenced cells prepared from fresh tissue, with cryopreserved cell suspensions displaying higher correlations with fresh tissue in gene expression. We showed that cryopreservation had minimal impacts on the results of downstream analyses such as biological pathway enrichment. For some tumours, cryopreservation modestly increased cell stress signatures compared to freshly analysed tissue. Further, we demonstrate the advantage of cryopreserving whole-cells for detecting cell-surface proteins using CITE-Seq, which is impossible using other preservation methods such as single nuclei-sequencing. We show that the viable cryopreservation of human cancers provides high-quality single-cells for multi-omics analysis. Our study guides new experimental designs for tissue biobanking for future clinical single-cell RNA sequencing studies.
Publisher: AMPCo
Date: 18-07-2019
DOI: 10.5694/MJA2.50280
Abstract: Representatives appointed by relevant Australian medical societies used a systematic approach for adaptation of guidelines (ADAPTE) to formulate clinical consensus recommendations on assessment and management of bone health in women with oestrogen receptor-positive early breast cancer receiving endocrine therapy. The current evidence suggests that women receiving adjuvant aromatase inhibitors and pre-menopausal woman treated with tamoxifen have accelerated bone loss and that women receiving adjuvant aromatase inhibitors have increased fracture risk. Both bisphosphonates and denosumab prevent bone loss additionally, denosumab has proven anti-fracture benefit in post-menopausal women receiving aromatase inhibitors for hormone receptor-positive breast cancer. Women considering endocrine therapy need fracture risk assessment, including clinical risk factors, biochemistry and bone mineral density measurement, with monitoring based on risk factors. Weight-bearing exercise and vitamin D and calcium sufficiency are recommended routinely. Anti-resorptive treatment is indicated in women with prevalent or incident clinical or morphometric fragility fractures, and should be considered in women with a T score (or Z score in women aged < 50 years) of < - 2.0 at any site, or if annual bone loss is ≥ 5%, considering baseline bone mineral density and other fracture risk factors. Duration of anti-resorptive treatment can be in idualised based on absolute fracture risk. Relative to their skeletal benefits, risks of adverse events with anti-resorptive treatments are low. Skeletal health should be considered in the decision-making process regarding choice and duration of endocrine therapy. Before and during endocrine therapy, skeletal health should be assessed regularly, optimised by non-pharmacological intervention and, where indicated, anti-resorptive treatment, in an in idualised, multidisciplinary approach.
Publisher: Elsevier BV
Date: 12-2020
Publisher: MDPI AG
Date: 05-06-2023
DOI: 10.20944/PREPRINTS202306.0232.V1
Abstract: Antibody-drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancers, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development [1]. Therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options [1-4]. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection [5-7]. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy and targeted agents are occurring.
Publisher: OMICS Publishing Group
Date: 2011
DOI: 10.4155/CLI.10.3
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in erse tissues, including in in idual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications.
Publisher: Springer Science and Business Media LLC
Date: 27-10-2015
DOI: 10.1038/NCOMMS9746
Abstract: Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-κB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance.
Publisher: Springer Science and Business Media LLC
Date: 08-2009
DOI: 10.1038/NM.2000
Abstract: Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from in iduals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem rogenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .
Publisher: Elsevier BV
Date: 09-2015
Publisher: Informa UK Limited
Date: 09-2022
DOI: 10.2147/DDDT.S380925
Publisher: MDPI AG
Date: 04-05-2022
Abstract: Inflammatory breast cancer (IBC) describes a highly aggressive form of breast cancer of erse molecular subtypes and clonal heterogeneity across in idual tumors. Accordingly, IBC is recognized by its clinical signs of inflammation, associated with expression of interleukin (IL)-6 and other inflammatory cytokines. Here, we investigate whether sub-clonal differences between expression of components of the IL-6 signaling cascade reveal a novel role for IL-6 to mediate a proliferative response in trans using two prototypical IBC cell lines. We find that SUM149 and SUM 190 cells faithfully replicate differential expression observed in a subset of human IBC specimens between IL-6, the activated form of the key downstream transcription factor STAT3, and of the HER2 receptor. Surprisingly, the high level of IL-6 produced by SUM149 cells activates STAT3 and stimulates proliferation in SUM190 cells, but not in SUM149 cells with low IL-6R expression. Importantly, SUM149 conditioned medium or co-culture with SUM149 cells induced growth of SUM190 cells, and this effect was abrogated by the IL-6R neutralizing antibody Tocilizumab. The results suggest a novel function for inter-clonal IL-6 signaling in IBC, whereby IL-6 promotes in trans proliferation of IL-6R and HER2-expressing responsive sub-clones and, therefore, may provide a vulnerability that can be exploited therapeutically by repurposing of a clinically approved antibody.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2015
DOI: 10.1038/NCOMMS10054
Abstract: Nature Communications 6: Article number: 8746 (2015) Published: 27 October 2015 Updated: 20 November 2015 The original version of this Article contained an error in the spelling of the author Yi Bao, which was incorrectly given as Bao Yi. This has now been corrected in both the PDF and HTML versions of the Article.
Publisher: Wiley
Date: 26-06-2006
Publisher: Springer Science and Business Media LLC
Date: 24-07-2018
DOI: 10.1038/S41467-018-05220-6
Abstract: The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.
Publisher: Cold Spring Harbor Laboratory
Date: 25-03-2013
Abstract: Androgen-stimulated growth of the molecular apocrine breast cancer subtype is mediated by an androgen receptor (AR)-regulated transcriptional program. However, the molecular details of this AR-centered regulatory network and the roles of other transcription factors that cooperate with AR in the network remain elusive. Here we report a positive feed-forward loop that enhances breast cancer growth involving AR, AR coregulators, and downstream target genes. In the absence of an androgen signal, TCF7L2 interacts with FOXA1 at AR-binding sites and represses the basal expression of AR target genes, including MYC . Direct AR regulation of MYC cooperates with AR-mediated activation of HER2/HER3 signaling. HER2/HER3 signaling increases the transcriptional activity of MYC through phosphorylation of MAD1, leading to increased levels of MYC/MAX heterodimers. MYC in turn reinforces the transcriptional activation of androgen-responsive genes. These results reveal a novel regulatory network in molecular apocrine breast cancers regulated by androgen and AR in which MYC plays a central role as both a key target and a cooperating transcription factor to drive oncogenic growth.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-05-2019
Abstract: Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER + mature luminal mammary epithelial cells and ER + breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancer-specific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER + breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with ER + breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics.
Publisher: OMICS Publishing Group
Date: 10-2012
DOI: 10.4155/CLI.12.88
Publisher: Springer Science and Business Media LLC
Date: 06-08-2022
DOI: 10.1038/S41467-022-32255-7
Abstract: The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.
Publisher: EMBO
Date: 13-08-2020
Publisher: Elsevier BV
Date: 08-2014
Publisher: Springer Science and Business Media LLC
Date: 08-08-2023
Publisher: Wiley
Date: 14-06-2018
DOI: 10.1111/CEN.13735
Abstract: To formulate clinical consensus recommendations on bone health assessment and management of women with oestrogen receptor-positive early breast cancer receiving endocrine therapy, representatives appointed by relevant Australian Medical Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing 5 key questions. Women receiving adjuvant aromatase inhibitors and the subset of premenopausal woman treated with tamoxifen have accelerated bone loss and increased fracture risk. Both bisphosphonates and denosumab prevent bone loss additionally, denosumab has proven antifracture benefit. Women considering endocrine therapy need fracture risk assessment, including clinical risk factors, biochemistry and bone mineral density (BMD) measurement, with monitoring based on risk factors. Weight-bearing exercise, vitamin D and calcium sufficiency are recommended routinely. Antiresorptive treatment should be considered in women with prevalent or incident clinical or morphometric fractures, a T-score (or Z-scores in women <50 years) of <-2.0 at any site, or if annual bone loss is ≥5%, considering baseline BMD and other fracture risk factors. Duration of antiresorptive treatment can be in idualized based on absolute fracture risk. Relative to their skeletal benefits, risks of adverse events with antiresorptive treatments are low. Skeletal health should be considered in the decision-making process regarding choice and duration of endocrine therapy. Before and during endocrine therapy, skeletal health should be assessed regularly, optimized by nonpharmacological intervention and where indicated antiresorptive treatment, in an in idualized, multidisciplinary approach. Clinical trials are needed to better delineate long-term fracture risks of adjuvant endocrine therapy and to determine the efficacy of interventions designed to minimize these risks.
Publisher: Bioscientifica
Date: 07-2017
DOI: 10.1530/ERC-16-0404E
Publisher: Elsevier BV
Date: 03-2018
Publisher: American Association for Cancer Research (AACR)
Date: 2016
DOI: 10.1158/2159-8290.CD-15-0341
Abstract: An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly lified across 18% of cancers, and many cancer cell lines have lified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy-number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12C-addicted cell line after KRAS downregulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly lified oncogene with an unusual epigenetic mode of action. Significance: MECP2 is a commonly lified oncogene in human malignancies with a unique epigenetic mechanism of action. Cancer Discov 6(1) 45–58. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1
Publisher: Springer Science and Business Media LLC
Date: 03-08-2021
DOI: 10.1186/S13058-021-01461-4
Abstract: Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue s les and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 lification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and lification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.
Publisher: Wiley
Date: 26-06-2020
DOI: 10.1111/CEN.14263
Publisher: Bioscientifica
Date: 05-2020
DOI: 10.1530/ERC-19-0501
Abstract: Cyclin E1 is one the most promising biomarkers in estrogen receptor positive (ER+) breast cancer for response to the new standard of care drug class, CDK4/6 inhibitors. Because of its strong predictive value, cyclin E1 expression may be used in the future to triage patients into potential responders and non-responders. Importantly, cyclin E1 is highly related to cyclin E2, and both cyclin E1 and cyclin E2 are estrogen target genes that can facilitate anti-estrogen resistance and can be highly expressed in breast cancer. However cyclin E1 and E2 are often expressed in different subsets of patients. This raises questions about whether the expression of cyclin E1 and cyclin E2 have different biological drivers, if high expressing subsets represent different clinical subtypes, and how to effectively develop a biomarker for E-cyclin expression. Finally, several pan-CDK inhibitors that target cyclin E-CDK2 activity have reached Phase II clinical trials. In this review, we outline the data identifying that different cohorts of patients have high expression of cyclins E1 and E2 in ER+ cancer and address the implications for biomarker and therapeutic development.
Publisher: Wiley
Date: 09-2016
DOI: 10.1111/CEN.13172
Abstract: Adjuvant endocrine therapy provides oncological benefits in women with early oestrogen-receptor-positive breast cancer, but has adverse effects consequent to induced oestradiol deficiency. Bone loss is accelerated, predisposing to increased fracture risk. Metabolic effects include changes in lipid metabolism and body composition although effects on cardiovascular risk are still unclear. Women commencing endocrine therapy should be proactively counselled about and monitored for these and other therapy-related complications including arthralgia and vasomotor symptoms. We provide strategies for prevention and management of these adverse effects, based, where available, on randomized controlled trial evidence specific to breast cancer survivors receiving endocrine treatment.
Publisher: MDPI AG
Date: 22-06-2022
DOI: 10.3390/PH15070772
Abstract: Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential of [64Cu]Cu-Sarcophagine (SAR)-Bombesin PET/CT (BBN) in re-staging metastatic ER+/PR+/human epidermal growth-factor-2-negative (HER2-) breast cancer. Seven patients with metastatic ER+/PR+/HER2- breast cancer undergoing staging underwent [64Cu]Cu-SAR-BBN PET-CT. Bloods, vital signs and electrocardiogram, blood tracer-clearance and dosimetry were undertaken. GRPR status was assessed in available metastatic biopsy s les. Staging with conventional imaging ([18F]FDG, bone scan and diagnostic CT) was within 3 weeks of [64Cu]Cu-SAR-BBN PET/CT. PET scans were assessed visually and quantitatively. Seven patients underwent imaging. One of the seven had de-novo metastatic breast cancer and six of the seven recurrent metastatic disease. Two of the seven had lobular subtype. No adverse events were reported. All seven patients were positive on conventional imaging (six of seven on FDG). [64Cu]Cu-SAR-BBN imaging was positive in five of the seven. Both [64Cu]Cu-SAR-BBN-negative patients had disease identified on [18F]FDG. One patient was [64Cu]Cu-SAR-BBN positive/[18F]FDG negative. Four of seven patients were [64Cu]Cu-SAR-BBN positive/[18F]FDG positive. In these four, mean SUVmax was higher for [64Cu]Cu-SAR-BBN than [18F]FDG (SUVmax 15 vs. 12). In the classical lobular subtype (two of seven), [64Cu]Cu-SAR-BBN was more avid compared to [18F]FDG (SUVmax 20 vs. 11, and 20 vs. ). Dosimetry calculations estimated whole-body effective dose for 200 MBq of [64Cu]Cu-SAR-BBN to be 1.9 mSv. [64Cu]Cu-SAR-BBN PET/CT appears safe and may have diagnostic value in metastatic ER+/PR+/HER2- breast cancer, particularly the lobular subtype. Further evaluation is warranted.
Publisher: Bioscientifica
Date: 04-2017
DOI: 10.1530/ERC-16-0404
Abstract: A cancer cell-centric view has long dominated the field of cancer biology. Research efforts have focussed on aberrant cancer cell signalling pathways and on changes to cancer cell DNA. Mounting evidence demonstrates that many cancer-associated cell types within the tumour stroma co-evolve and support tumour growth and development, greatly modifying cancer cell behaviour, facilitating invasion and metastasis and controlling dormancy and sensitivity to drug therapy. Thus, these stromal cells represent potential targets for cancer therapy. Among these cell types, immune cells have emerged as a promising target for therapy. The adaptive and the innate immune system play an important role in normal mammary development and breast cancer. The number of infiltrating adaptive immune system cells with tumour-rejecting capacity, primarily, T lymphocytes, is lower in breast cancer compared with other cancer types, but infiltration occurs in a large proportion of cases. There is strong evidence demonstrating the importance of the immunosuppressive role of the innate immune system during breast cancer progression. A consideration of components of both the innate and the adaptive immune system is essential for the design and development of immunotherapies in breast cancer. In this review, we focus on the importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) as potential targets for breast cancer therapy.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2021
DOI: 10.1038/S41591-020-01168-7
Abstract: The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a erse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2014
DOI: 10.1158/2159-8290.CD-13-0891
Abstract: BRCA1 promotes homologous recombination–mediated DNA repair (HRR). However, HRR must be tightly regulated to prevent illegitimate recombination. We previously found that BRCA1 HRR function is regulated by the RAP80 complex, but the mechanism was unclear. We have now observed that PARP1 interacts with and poly-ADP-ribosylates (aka PARsylates) BRCA1. PARsylation is directed at the BRCA1 DNA binding domain and downmodulates its function. Moreover, RAP80 contains a poly-ADP-ribose–interacting domain that binds PARsylated BRCA1 and helps to maintain the stability of PARP1–BRCA1–RAP80 complexes. BRCA1 PARsylation is a key step in BRCA1 HRR control. When BRCA1 PARsylation is defective, it gives rise to excessive HRR and manifestations of genome instability. BRCA1 PARsylation and/or RAP80 expression is defective in a subset of sporadic breast cancer cell lines and patient-derived tumor xenograft models. These observations are consistent with the possibility that such defects, when chronic, contribute to tumor development in BRCA1+/+ in iduals. Significance: We propose a model that describes how BRCA1 functions to both support and restrict HRR. BRCA1 PARsylation is a key event in this process, failure of which triggers hyper-recombination and chromosome instability. Thus, hyperfunctioning BRCA1 can elicit genomic abnormalities similar to those observed in the absence of certain BRCA1 functions. Cancer Discov 4(12) 1430–47. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1355
Publisher: Informa UK Limited
Date: 02-11-2017
Publisher: MDPI AG
Date: 13-05-2022
Abstract: The development of therapies that target specific disease subtypes has dramatically improved outcomes for patients with breast cancer. However, survival gains have not been uniform across patients, even within a given molecular subtype. Large collections of publicly available drug screening data matched with transcriptomic measurements have facilitated the development of computational models that predict response to therapy. Here, we generated a series of predictive gene signatures to estimate the sensitivity of breast cancer s les to 90 drugs, comprising FDA-approved drugs or compounds in early development. To achieve this, we used a cell line-based drug screen with matched transcriptomic data to derive in silico models that we validated in large independent datasets obtained from cell lines and patient-derived xenograft (PDX) models. Robust computational signatures were obtained for 28 drugs and used to predict drug efficacy in a set of PDX models. We found that our signature for cisplatin can be used to identify tumors that are likely to respond to this drug, even in absence of the BRCA-1 mutation routinely used to select patients for platinum-based therapies. This clinically relevant observation was confirmed in multiple PDXs. Our study foreshadows an effective delivery approach for precision medicine.
Publisher: eLife Sciences Publications, Ltd
Date: 12-03-2018
DOI: 10.7554/ELIFE.36414
Publisher: Frontiers Media SA
Date: 03-11-2021
Abstract: With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possibility of targeting the p53/MDM2 via inhibition of MDM2 in the CDK4/6i resistance setting.
Publisher: MDPI AG
Date: 26-07-2023
DOI: 10.3390/PHARMACEUTICS15082017
Abstract: Antibody–drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancer, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development. The therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy, and targeted agents are occurring.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2006
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2023
DOI: 10.1101/2023.04.06.535805
Abstract: Spatial transcriptomic technologies are powerful tools for resolving the spatial heterogeneity of gene expression in tissue s les. However, little evidence exists on relative strengths and weaknesses of the various available technologies for profiling human tumour tissue. In this study, we aimed to provide an objective assessment of two common spatial transcriptomics platforms, 10X Genomics’ Visium and Nanostring’s GeoMx DSP. The abilities of the DSP and Visium platforms to profile transcriptomic features were compared using matching cell line and primary breast cancer tissue s les. A head-to-head comparison was conducted using data generated from matching s les and synthetic tissue references. Platform specific features were also assessed according to manufacturers’ recommendations to evaluate the optimal usage of the two technologies. We identified substantial variations in assay design between the DSP and Visium assays such as transcriptomic coverage and composition of the transcripts detected. When the data was standardised according to manufacturers’ recommendations, the DSP platform was more sensitive in gene expression detection. However, its specificity was diminished by the presence of non-specific detection. Our results also confirmed the strength and weakness of each platform in characterising spatial transcriptomic features of tissue s les, in particular their application to hypothesis generation versus hypothesis testing. In this study, we share our experience on both DSP and Visium technologies as end users. We hope this can guide future users to choose the most suitable platform for their research. In addition, this dataset can be used as an important resource for the development of new analysis tools.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2019
Location: Australia
Location: Australia
Start Date: 2020
End Date: 2023
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2027
Funder: National Breast Cancer Foundation
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: National Breast Cancer Foundation
View Funded ActivityStart Date: 2019
End Date: 2021
Funder: National Breast Cancer Foundation
View Funded ActivityStart Date: 2019
End Date: 2021
Funder: National Breast Cancer Foundation
View Funded ActivityStart Date: 2017
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Breast Cancer Foundation
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded Activity