ORCID Profile
0000-0001-8093-8733
Current Organisation
The University of Auckland
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Publisher: No publisher found
Date: 2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-01-2017
DOI: 10.1158/0008-5472.CAN-16-2025
Abstract: Beyond prophylactic mastectomy, there are currently very few options available to BRCA1 mutation carriers to help reduce their risk of developing breast cancer. An effective prevention therapy therefore remains a pressing area of need. Accumulating evidence points to lification of the progesterone signaling axis in precancerous tissue from BRCA1 mutation carriers. Given that RANKL is an important paracrine mediator of hormonal signaling in breast tissue, there has been considerable interest in exploring a potential role for this pathway in oncogenesis. Recent findings indicate that the RANK and NF-κB pathways are aberrantly activated in luminal progenitor cells resident in preneoplastic BRCA1mut/+ breast tissue. The augmented proliferation of these cells and their predilection for DNA damage suggest that they are prime cellular targets for basal-like cancers arising in BRCA1 mutation carriers. The end result is a hyperactive pathway, initiated by progesterone and lified by DNA damage–induced NF-κB signaling, that likely accounts for the susceptibility of BRCA1mut/+ luminal progenitor cells to oncogenesis and tissue specificity. Specific targeting of this progenitor subset has revealed a compelling new prevention strategy for these and possibly other high-risk women. Cancer Res 77(3) 595–600. ©2017 AACR.
Publisher: Elsevier BV
Date: 10-2022
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-06-2017
DOI: 10.1126/SCITRANSLMED.AAL4922
Abstract: BRCA1 -mutated tumors may be particularly vulnerable to dual checkpoint inhibition.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/NM.4118
Abstract: In iduals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11 also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2019
Publisher: Elsevier BV
Date: 07-2016
Publisher: Springer Science and Business Media LLC
Date: 11-12-2020
Publisher: Oxford University Press (OUP)
Date: 04-04-2017
DOI: 10.1093/JNCI/DJX038
Publisher: American Physiological Society
Date: 04-2019
DOI: 10.1152/PHYSREV.00040.2018
Abstract: The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by dedicated stem and progenitor cells. Both short- and long-lived lineage-restricted progenitors have been identified in adult tissue as well as a small pool of multipotent mammary stem cells (MaSCs), reflecting intrinsic complexity within the epithelial hierarchy. While unipotent progenitor cells predominantly execute day-to-day homeostasis and postnatal morphogenesis during puberty and pregnancy, multipotent MaSCs have been implicated in coordinating alveologenesis and long-term ductal maintenance. Nonetheless, the multipotency of stem cells in the adult remains controversial. The advent of large-scale single-cell molecular profiling has revealed striking changes in the gene expression landscape through ontogeny and the presence of transient intermediate populations. An increasing number of lineage cell-fate determination factors and potential niche regulators have now been mapped along the hierarchy, with many implicated in breast carcinogenesis. The emerging ersity among stem and progenitor populations of the mammary epithelium is likely to underpin the heterogeneity that characterizes breast cancer.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.CCELL.2019.02.010
Abstract: Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Expression profiling of clones arising in Pten/Trp53-deficient tumors identified distinct molecular signatures. Strikingly, most clones harbored cells that had undergone an epithelial-to-mesenchymal transition, indicating widespread, inherent plasticity. Hence, an integrative pipeline that combines lineage tracing, 3D imaging, and clonal RNA sequencing technologies offers a comprehensive path for studying mechanisms underlying heterogeneity in whole tumors.
Publisher: Springer Science and Business Media LLC
Date: 02-02-2023
Publisher: Springer Science and Business Media LLC
Date: 24-02-2022
Publisher: BMJ
Date: 10-2022
DOI: 10.1136/BMJPO-2022-001657
Abstract: The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries. The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria. A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)). Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Springer Science and Business Media LLC
Date: 11-06-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
No related grants have been discovered for Emma Nolan.