ORCID Profile
0000-0003-3116-2902
Current Organisation
University of Adelaide
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Publisher: Wiley
Date: 19-02-2009
DOI: 10.2164/JANDROL.108.006569
Abstract: The cytokine transforming growth factor beta1 (TGFB1) is implicated in male sexual function. Previous behavioral studies show that Tgfb1 null mutant mice mount and display limited intromission behavior with receptive females but are unable to complete successful copulation. The studies presented here explore the physiologic basis for sexual dysfunction in Tgfb1 null mutant males. Scanning electron microscopy revealed that the surface of the penis in Tgfb1 null mutant males was abnormally coated in superficial keratinized epithelial cells. There was a significant reduction in protrusion of penile spines through the superficial tissue in Tgfb1 null mutant mice in some mice, the spines were almost completely embedded. Histologic analysis revealed reduced skin thickness in the penis of Tgfb1 null mutant males. Nerve fibers, endothelial cells, smooth muscle actin, macrophages, and neuronal and inducible nitric oxide synthase were present in similar abundance and location in Tgfb1 null mutant mice compared with wild-type controls however, an increase in collagen I deposition was detected. Behavioral studies revealed that Tgfb1 null mutant males undergo spontaneous noncontact erections, albeit at a reduced rate compared with control mice, and engage in less frequent genital grooming activity. These studies suggest that Tgfb1 null mutation may adversely influence copulatory behavior through effects on both altered structural integrity of the penile skin and impaired tissue compliance leading to erectile dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 18-08-2020
DOI: 10.1186/S13058-020-01327-1
Abstract: The Oncotype DX 21-gene Recurrence Score is a genomic-based algorithm that guides adjuvant chemotherapy treatment decisions for women with early-stage, oestrogen receptor (ER)-positive breast cancer. However, there are age-related differences in chemotherapy benefit for women with intermediate Oncotype DX Recurrence Scores that are not well understood. Menstrual cycling in younger women is associated with hormonal fluctuations that might affect the expression of genomic predictive biomarkers and alter Recurrence Scores. Here, we use paired human breast cancer s les to demonstrate that the clinically employed Oncotype DX algorithm is critically affected by patient age. RNA was extracted from 25 pairs of formalin-fixed paraffin-embedded, invasive ER-positive breast cancer s les that had been collected approximately 2 weeks apart. A 21-gene signature analogous to the Oncotype DX platform was assessed through quantitative real-time PCR, and experimental recurrence scores were calculated using the Oncotype DX algorithm. There was a significant inverse association between patient age and discordance in the recurrence score. For every 1-year decrease in age, discordance in recurrence scores between paired s les increased by 0.08 units (95% CI − 0.14, − 0.01 p = 0.017). Discordance in recurrence scores for women under the age of 50 was driven primarily by proliferation- and HER2-associated genes. The Oncotype DX 21-gene Recurrence Score algorithm is critically affected by patient age. These findings emphasise the need for the consideration of patient age, particularly for women younger than 50, in the development and application of genomic-based algorithms for breast cancer care.
Publisher: Springer Science and Business Media LLC
Date: 07-2014
DOI: 10.1007/S10911-014-9324-X
Abstract: It is well established that the development and homeostasis of the mammary gland are highly dependent upon the actions of ovarian hormones progesterone and estrogen, as well as the availability of prolactin for the pregnant and lactating gland. More recently it has become apparent that immune system cells and cytokines play essential roles in both mammary gland development as well as breast cancer. Here, we review hormonal effects on mammary gland biology during puberty, menstrual cycling, pregnancy, lactation and involution, and dissect how hormonal control of the immune system may contribute to mammary development at each stage via cytokine secretion and recruitment of macrophages, eosinophils, mast cells and lymphocytes. Collectively, these alterations may create an immunotolerant or inflammatory immune environment at specific developmental stages or phases of the menstrual cycle. Of particular interest for further research is investigation of the combinatorial actions of progesterone and estrogen during the luteal phase of the menstrual cycle and key developmental points where the immune system may play an active role both in mammary development as well as in the creation of an immunotolerant environment, thereby affecting breast cancer risk.
Publisher: Ecancer Global Foundation
Date: 06-02-2201
Publisher: Springer Science and Business Media LLC
Date: 11-03-2014
DOI: 10.1007/S10549-014-2901-2
Abstract: There has been considerable recent interest in the genetic, biological and epidemiological basis of mammographic density (MD), and the search for causative links between MD and breast cancer (BC) risk. This report will critically review the current literature on MD and summarize the current evidence for its association with BC. Keywords 'mammographic dens*', 'dense mammary tissue' or 'percent dens*' were used to search the existing literature in English on PubMed and Medline. All reports were critically analyzed. The data were assigned to one of the following aspects of MD: general association with BC, its relationship with the breast hormonal milieu, the cellular basis of MD, the generic variations of MD, and its significance in the clinical setting. MD adjusted for age, and BMI is associated with increased risk of BC diagnosis, advanced tumour stage at diagnosis and increased risk of both local recurrence and second primary cancers. The MD measures that predict BC risk have high heritability, and to date several genetic markers associated with BC risk have been found to also be associated with these MD risk predictors. Change in MD could be a predictor of the extent of chemoprevention with tamoxifen. Although the biological and genetic pathways that determine and perhaps modulate MD remain largely unresolved, significant inroads are being made into the understanding of MD, which may lead to benefits in clinical screening, assessment and treatment strategies. This review provides a timely update on the current understanding of MD's association with BC risk.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.CYTOGFR.2009.05.003
Abstract: Transforming growth factor beta 1 (TGFB1) is implicated as a key regulator of the development and cyclic remodelling characteristic of reproductive tissues. The physiological significance of TGFB1 in reproductive biology and fertility has been extensively examined in Tgfb1 null mutant mice. Genetic deficiency in TGFB1 causes perturbed functioning of the hypothalamic-pituitary-gonadal axis, inhibiting luteinising hormone (LH) synthesis and leading to downstream effects on testosterone production in males and estrous cycle abnormalities in females. Oocyte developmental incompetence, accompanied by early embryo arrest as well as altered pubertal mammary gland morphogenesis are observed. In addition to LH and testosterone deficiency, male Tgfb1 null mice demonstrate complete inability to mate with females, associated with failure to initiate and/or sustain successful penile intromission or ejaculation. These studies demonstrate the profound significance of TGFB1 in male and female reproductive physiology, and provide a foundation for exploring the significance of this cytokine in human infertility and sexual dysfunction.
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0165-0378(02)00015-3
Abstract: TGFbeta is a potent immune deviating agent, driving active forms of immune tolerance in peripheral tissues through effects on the induction and resolution of inflammatory responses and phenotype skewing in antigen-presenting cells and lymphocytes. The TGFbeta content of seminal plasma from human, rodent and livestock species is amongst the highest measured in biological fluids. The seminal vesicle gland is the principal source of TGFbeta in the semen of mice, where its synthesis is regulated by testosterone. At insemination, seminal TGFbeta is deposited in the female tract and is activated by acidic vaginal pH, enzymes of male or female tract origin, or through cleavage-independent processes involving conformational change after interaction with epithelial cell docking proteins. Seminal TGFbeta has been shown to be a principal stimulating agent in the post-coital inflammatory response, and is likely to be essential for induction of immune tolerance to seminal antigens. As well as preventing aberrant immunity to spermatozoa, these events are implicated in priming an appropriate female immune response to embryo implantation, since many seminal antigens are shared by the conceptus. The cascade of immunological events elicited by seminal TGFbeta may therefore explain epidemiological observations linking acute and cumulative exposure to semen with successful placental development and pregnancy outcome. Depending on whether the female tract has evolved mechanisms to discriminate seminal antigens from opportunistic pathogens, there may be a detrimental cost of seminal TGFbeta in inhibiting protective immunity to agents of sexually transmitted disease including HIV. A better understanding of the significance and role of TGFbeta in semen will facilitate development of novel therapies for immune-based infertility disorders.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JRI.2019.01.002
Abstract: Endometriotic lesion development involves complex interactions between endometrial tissue, the peritoneum and immune cells. Macrophages are essential in this process however their precise roles are not defined. To investigate whether infiltrating macrophages acquire functionally different phenotypes during lesion development, human endometrial tissues were grafted into immunodeficient mice expressing macrophage-specific green fluorescent protein (GFP). Although the numbers of GFP-positive macrophages were similar in lesions 4, 7, 10 and 14 days after grafting, their surface markers changed over time. Inflammatory markers MHC class II (MHC II) and iNOS were present on 36% and 41% of macrophages respectively early in lesion development at day 4, whereas abundance of tissue remodelling markers peaked later, with arginase 1 most highly expressed on 57% of macrophages at day 7 and scavenger receptor A (CD204) on 66% of macrophages at day 14. This is consistent with a transition from classical M1 macrophage activity to an alternate M2 profile, which correlates to histological hallmarks of initially acute inflammation followed by tissue remodelling during lesion development. This progressive shift in phenotype is likely to be relevant to the mechanisms by which macrophages are central players in endometriosis-like lesion development.
Publisher: Springer Science and Business Media LLC
Date: 04-06-2015
Publisher: Springer Science and Business Media LLC
Date: 11-01-2017
Publisher: CSIRO Publishing
Date: 2020
DOI: 10.1071/RD19378
Abstract: Female mice heterozygous for a genetic mutation in transcription factor forkhead box p3 (Foxp3) spontaneously develop mammary cancers however, the underlying mechanism is not well understood. We hypothesised that increased cancer susceptibility is associated with an underlying perturbation in mammary gland development. The role of Foxp3 in mammary ductal morphogenesis was investigated in heterozygous Foxp3Sf/+ and wildtype Foxp3+/+ mice during puberty and at specific stages of the oestrous cycle. No differences in mammary ductal branching morphogenesis, terminal end bud formation or ductal elongation were observed in pubertal Foxp3Sf/+ mice compared with Foxp3+/+ mice. During adulthood, all mice underwent normal regular oestrous cycles. No differences in epithelial branching morphology were detected in mammary glands from mice at the oestrus, metoestrus, dioestrus and pro-oestrus stages of the cycle. Furthermore, abundance of Foxp3 mRNA and protein in the mammary gland and lymph nodes was not altered in Foxp3Sf/+ mice compared with Foxp3+/+ mice. These studies suggest that Foxp3 heterozygosity does not overtly affect mammary gland development during puberty or the oestrous cycle. Further studies are required to dissect the underlying mechanisms of increased mammary cancer susceptibility in Foxp3Sf/+ heterozygous mice and the function of this transcription factor in normal mammary gland development.
Publisher: MDPI AG
Date: 02-02-2022
DOI: 10.3390/JCM11030799
Abstract: Mammographic density is associated with a 4–6-fold increase in breast cancer risk independent of age and BMI. High mammographic density is characterized by breast tissue with high proportions of stroma comprised of fibroblasts, collagen, and immune cells. This study sought to investigate whether stromal fibroblasts from high mammographic density breast tissue contributes to increased extracellular matrix deposition and pro-tumorigenic signaling. Mammary fibroblasts were isolated from women with high and low mammographic density and exposed to immune factors myeloperoxidase (MPO), eosinophil peroxidase (EPO), transforming growth factor beta 1 (TGFB1) and tumour necrosis factor alpha (TNFA) for 72 h and profiled for expression of cancer-associated fibroblast and extracellular matrix regulation markers. No differences in gene expression profiles or collagen production were observed between fibroblasts with high or low mammographic density, and they did not have a differential response to immune mediators. MPO and EPO significantly increased the production of collagen 1. TGFB and TNFA induced variable changes in gene expression. Fibroblasts cultured in vitro from women with high mammographic density do not appear to be inherently different to those from women with low mammographic density. The function of fibroblasts in mammographic density-associated breast cancer risk is likely to be regulated by immune signals from surrounding cells in the microenvironment.
Publisher: Oxford University Press (OUP)
Date: 05-2014
DOI: 10.1095/BIOLREPROD.114.117663
Abstract: Lactation mastitis is a debilitating inflammatory breast disease in postpartum women. Disease severity is associated with markers of inflammation rather than bacterial load, suggesting that immune-signaling pathways activated in the host are important in the disease pathology. The role of the innate pattern recognition receptor toll-like receptor 4 (TLR4) in progression and resolution of mastitislike disease was investigated in a mouse model. Lipopolysaccharide in Matrigel (10 μg/10 μl) was administered into the teat canal of lactating Tlr4 null mutant and wild-type mice to induce a localized area of inflammation. Mastitis induction resulted in a marked influx of RB6-positive neutrophils and F4/80-positive macrophages, which was higher in Tlr4(-/-) mice compared to wild-type mice. Tlr4 null mutation resulted in an altered immune-signaling fingerprint following induction of mastitis, with attenuated serum cytokines, including CXCL1, CCL2, interleukin 1 beta, and tumor necrosis factor alpha compared to wild-type mice. In both genotypes, the localized area of inflammation had resolved after 7 days, and milk protein was evident. However, the mammary glands of wild-type mice exhibited reduced capacity for milk production, with decreased percent area populated with glandular epithelium and decreased abundance of nuclear phosphorylated signal transducer and activator of transcription 5 compared to Tlr4 null mice. This study demonstrates that inflammatory pathways activated in the host are critically important in mastitis disease progression and suggests that lactation insufficiency associated with mastitis may be a consequence of TLR4-mediated inflammation, rather than the bacterial infection itself.
Publisher: MDPI AG
Date: 19-02-2022
Abstract: The COVID-19 pandemic caused many scientific conferences to move online, posing a great challenge for scientific communication. This change offers potential advantages and disadvantages for inclusion, ersity, and scientific advancement. Here, we analyse participants’ experiences of the Why Study Mammographic Density? Conference to explore some of these issues and identify key points of contention between different stakeholders. We found that while increasing participant ersity is facilitated by online conferencing, if the participants cannot interact informally with each other, there is value which is lost. In returning to in-person conferences, it will be important not to “shut the door” on those whose participation was enabled by the online format.
Publisher: CSIRO Publishing
Date: 2009
DOI: 10.1071/RD08294
Abstract: Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor β1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2 however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (~150 μg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.SEMCDB.2020.11.011
Abstract: Mammographic density refers to the radiological appearance of fibroglandular and adipose tissue on a mammogram of the breast. Women with relatively high mammographic density for their age and body mass index are at significantly higher risk for breast cancer. The association between mammographic density and breast cancer risk is well-established, however the molecular and cellular events that lead to the development of high mammographic density are yet to be elucidated. Puberty is a critical time for breast development, where endocrine and paracrine signalling drive development of the mammary gland epithelium, stroma, and adipose tissue. As the relative abundance of these cell types determines the radiological appearance of the adult breast, puberty should be considered as a key developmental stage in the establishment of mammographic density. Epidemiological studies have pointed to the significance of pubertal adipose tissue deposition, as well as timing of menarche and thelarche, on adult mammographic density and breast cancer risk. Activation of hypothalamic-pituitary axes during puberty combined with genetic and epigenetic molecular determinants, together with stromal fibroblasts, extracellular matrix, and immune signalling factors in the mammary gland, act in concert to drive breast development and the relative abundance of different cell types in the adult breast. Here, we discuss the key cellular and molecular mechanisms through which pubertal mammary gland development may affect adult mammographic density and cancer risk.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2014
DOI: 10.1007/S10911-014-9325-9
Abstract: Mastitis is a common inflammatory disease during lactation that causes reduced milk supply. A growing body of evidence challenges the central role of pathogenic bacteria in mastitis, with disease severity associated with markers of inflammation rather than infection. Inflammation in the mammary gland may be triggered by microbe-associated molecular patterns (MAMPs) as well as danger-associated molecular patterns (DAMPs) binding to pattern recognition receptors such as the toll-like receptors (TLRs) on the surface of mammary epithelial cells and local immune cell populations. Activation of the TLR4 signalling pathway and downstream nuclear factor kappa B (NFkB) is critical to mediating local mammary gland inflammation and systemic immune responses in mouse models of mastitis. However, activation of NFkB also induces epithelial cell apoptosis and reduced milk protein synthesis, suggesting that inflammatory mediators activated during mastitis promote partial involution. Perturbed milk flow, maternal stress and genetic predisposition are significant risk factors for mastitis, and could lead to a heightened TLR4-mediated inflammatory response, resulting in increased susceptibility and severity of mastitis disease in the context of low MAMP abundance. Therefore, heightened host inflammatory signalling may act in concert with pathogenic or commensal bacterial species to cause both the inflammation associated with mastitis and lactation insufficiency. Here, we present an alternate paradigm to the widely held notion that breast inflammation is driven principally by infectious bacterial pathogens, and suggest there may be other therapeutic strategies, apart from the currently utilised antimicrobial agents, that could be employed to prevent and treat mastitis in women.
Publisher: Springer Science and Business Media LLC
Date: 07-2014
Publisher: Frontiers Media SA
Date: 04-12-2017
Publisher: MDPI AG
Date: 27-10-2021
Abstract: Mammographic density is an important risk factor for breast cancer women with extremely dense breasts have a four to six fold increased risk of breast cancer compared to women with mostly fatty breasts, when matched with age and body mass index. High mammographic density is characterised by high proportions of stroma, containing fibroblasts, collagen and immune cells that suggest a pro-tumour inflammatory microenvironment. However, the biological mechanisms that drive increased mammographic density and the associated increased risk of breast cancer are not yet understood. Inflammatory factors such as monocyte chemotactic protein 1, peroxidase enzymes, transforming growth factor beta, and tumour necrosis factor alpha have been implicated in breast development as well as breast cancer risk, and also influence functions of stromal fibroblasts. Here, the current knowledge and understanding of the underlying biological mechanisms that lead to high mammographic density and the associated increased risk of breast cancer are reviewed, with particular consideration to potential immune factors that may contribute to this process.
Publisher: Elsevier BV
Date: 12-2011
Publisher: Elsevier BV
Date: 06-2000
DOI: 10.1016/S0303-7207(00)00240-9
Abstract: Inhibition of insulin-like growth factor (IGF)-I induced DNA synthesis in bovine oocyte-cumulus complexes (OCCs) caused by follicle-stimulating hormone (FSH) has been linked to changes in the extracellular matrix which do not occur in mural granulosa cells (MGCs). We investigated regulation by IGF-I and FSH of secreted and extracellular matrix entrapped IGF-binding proteins. OCCs and MGCs from bovine ovaries were cultured in media supplemented with IGF-I and FSH for 24 h. Culture media and extracellular matrix were analysed for IGF-binding proteins by Western ligand blot and immunoblot and found to contain principally IGFBP-3 and -5. The combined treatment of IGF-I and FSH increased the concentration of IGFBP-3 in OCC and MGC conditioned media by 4- and 6-fold, respectively. Treatment of OCCs and not MGCs with IGF-I and FSH together increased extracellular matrix IGFBP-5 by 2.5-fold. The differential regulation of extracellular matrix IGFBP-5 in OCCs compared to MGCs suggest involvement of changes in the extracellular matrix brought about by IGF-I and FSH in overall regulation of IGF-I in the ovarian follicle.
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: Wiley
Date: 09-01-2016
DOI: 10.1002/CAM4.599
Publisher: Elsevier BV
Date: 05-2021
DOI: 10.1016/J.EARLHUMDEV.2021.105342
Abstract: Many women report low milk supply as the reason for premature breastfeeding cessation. Altered mammary gland development may impact a woman's lactation ability. This review identifies modern exogenous exposures which alter mammary gland development during embryonic life, puberty and pregnancy. A systematic review was undertaken whereby Medline, CINAHL and Embase articles published from January 1, 2005 to November 20, 2020 were searched using the keywords puberty or embry* or fetal or foetal or foetus or fetus or pregnan* or gestation* AND "mammary gland development" or "breast development" or "mammary development" or "mammary gland function" or "mammary function" or "insufficient glandular tissue" or "mammary hypoplasia" or "breast hypoplasia" or "mammary gland hypoplasia" or "tubular breast*" or "tuberous breast*" or "glandular tissue" or "breast composition" or "mammary composition" or "mammary gland composition". After initial screening of 1207 records, 60 full texts were assessed for eligibility 6 were excluded due to lack of information about exposure or outcome, leaving 54 studies. The review included results from 52 animal (rats and mice, monkeys, rabbits, sheep, goats pigs and cows) and 2 human studies. Various endocrine disrupting chemicals and an obesogenic diet were found to be associated with altered mammary gland morphology during key development stages. To improve lactation outcomes, future studies need to focus on lactation as the endpoint and be conducted in a standardised manner to allow for a more significant contribution to the literature that allows for better comparison across studies.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.MCE.2016.11.007
Abstract: Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in abundance by innate immune infiltrates at sites of inflammation and injury. We have discovered new and previously unrecognised roles for heme peroxidases in extracellular matrix biosynthesis, angiogenesis, and bone mineralisation, all of which play an essential role in skeletal integrity. In this study we used in vitro models of osteoclastogenesis to investigate the effects of heme peroxidase enzymes on osteoclast differentiation and bone resorbing activity, pertinent to skeletal development and remodelling. Receptor activator of nuclear factor kappa B-ligand (RANKL) stimulates the formation of tartate-resistant acid phosphatase (TRAP) positive multinucleated cells and increases bone resorption when cultured with human peripheral blood mononuclear cells (PBMCs) or the RAW264.7 murine monocytic cell line. When RANKL was added in combination with either MPO or EPO, a dose-dependent inhibition of osteoclast differentiation and bone resorption was observed. Notably, peroxidases had no effect on the bone resorbing activity of mature osteoclasts, suggesting that the inhibitory effect of the peroxidases was limited to osteoclast precursor cells. Mechanistically, we observed that osteoclast precursor cells readily internalize peroxidases, and inhibited the phosphorylation of JNK, p38 MAPK and ERK1/2, important signalling molecules central to osteoclastogenesis. Our findings suggest that peroxidase enzymes, like MPO and EPO, may play a fundamental role in inhibiting RANKL-induced osteoclast differentiation at inflammatory sites of bone fracture and injury. Therefore, peroxidase enzymes could be considered as potential therapeutic agents to treat osteolytic bone disease and aberrant bone resorption.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2015
Publisher: Oxford University Press (OUP)
Date: 06-12-2007
Abstract: Cytokines play many erse and important roles in reproductive biology, and dissecting the complex interactions between these proteins and the different reproductive organs is a difficult task. One approach is to use gene ablation, or 'knockout', to analyse the effect of deletion of a single cytokine on mouse reproductive function. This review summarizes the essential roles of cytokines in reproductive biology that have been revealed by gene knockout studies, including development and regulation of the hypothalamo-pituitary-gondal axis, ovarian folliculogenesis, implantation and immune system modulation during pregnancy. However, successful utilization of this approach must consider the caveats associated with gene ablation studies, e.g. embryonic lethality, systemic effects of cytokine ablation on local reproductive processes and the limited exposure to pathogens in mice housed in laboratory conditions. New sophisticated technology that temporally or spatially regulates gene ablation can overcome some of these limitations. Discoveries on the roles of cytokines in reproductive function uncovered by gene ablation studies can now be applied to improve in vitro fertilization for infertile couples and in the development of contraceptive therapies.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2015
DOI: 10.1038/ONC.2015.66
Abstract: The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.BIOCEL.2015.09.006
Abstract: Peroxidases are heme-containing enzymes released by activated immune cells at sites of inflammation. To-date their functional role in human health has mainly been limited to providing a mechanism for oxidative defence against invading bacteria and other pathogenic microorganisms. Our laboratory has recently identified a new functional role for peroxidase enzymes in stimulating fibroblast migration and collagen biosynthesis, offering a new insight into the causative association between inflammation and the pro-fibrogenic events that mediate tissue repair and regeneration. Peroxidases are found at elevated levels within and near blood vessels however, their direct involvement in angiogenesis has never been reported. Here we report for the first time that myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are readily internalised by human umbilical vein endothelial cells (HUVEC) where they promote cellular proliferation, migration, invasion, and stimulate angiogenesis both in vitro and in vivo. These pro-angiogenic effects were attenuated using the specific peroxidase inhibitor 4-ABAH, indicating the enzyme's catalytic activity is essential in mediating this response. Mechanistically, we provide evidence that MPO and EPO regulate endothelial FAK, Akt, p38 MAPK, ERK1/2 phosphorylation and stabilisation of HIF-2α, culminating in transcriptional regulation of key angiogenesis pathways. These findings uncover for the first time an important and previously unsuspected role for peroxidases as drivers of angiogenesis, and suggest that peroxidase inhibitors may have therapeutic potential for the treatment of angiogenesis related diseases driven by inflammation.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2021
DOI: 10.1186/S12885-021-08496-Y
Abstract: The Oncotype DX 21-gene Recurrence Score is predictive of adjuvant chemotherapy benefit for women with early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. In premenopausal women, fluctuations in estrogen and progesterone during the menstrual cycle impact gene expression in hormone-responsive cancers. However, the extent to which menstrual cycling affects the Oncotype DX 21-gene signature remains unclear. Here, we investigate the impact of ovarian cycle stage on the 21-gene signature using a naturally cycling mouse model of breast cancer. ER-positive mammary tumours were dissected from naturally cycling Mmtv-Pymt mice at either the estrus or diestrus phase of the ovarian cycle. The Oncotype DX 21-gene signature was assessed through quantitative real time-PCR, and a 21-gene experimental recurrence score analogous to the Oncotype DX Recurrence Score was calculated. Tumours collected at diestrus exhibited significant differences in expression of 6 Oncotype DX signature genes ( Ki67 , Ccnb1 , Esr1 , Erbb2 , Grb7 , Bag1 p ≤ 0.05) and a significant increase in 21-gene recurrence score (21.8 ± 2.4 mean ± SEM) compared to tumours dissected at estrus (15.5 ± 1.9 p = 0.03). Clustering analysis revealed a subgroup of tumours collected at diestrus characterised by increased expression of proliferation- ( p 0.001) and invasion-group ( p = 0.01) genes, and increased 21-gene recurrence score ( p = 0.01). No correlation between ER, PR, HER2, and KI67 protein abundance measured by Western blot and abundance of mRNA for the corresponding gene was observed, suggesting that gene expression is more susceptible to hormone-induced fluctuation compared to protein expression. Ovarian cycle stage at the time of tissue collection critically affects the 21-gene signature in Mmtv-Pymt murine mammary tumours. Further studies are required to determine whether Oncotype DX Recurrence Scores in women are similarly affected by menstrual cycle stage.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.CYTO.2012.12.002
Abstract: Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates cell proliferation, apoptosis and immune system responses. In the breast, the mammary epithelium is the primary source of TGFB1 and increased expression is associated with increased breast cancer risk. This study was conducted to investigate the roles of epithelial cell-derived TGFB1 in regulation of epithelial cell activity and macrophage phenotype in the mammary gland. Tgfb1 null mutant and wildtype mammary epithelium was transplanted into contra-lateral sides of the cleared mammary gland of TGFB1 replete scid mice. Transplanted tissue was analysed for markers of proliferation and apoptosis to determine the effect of Tgfb1 null mutation on epithelial cell turnover, and was analysed by immunohistochemistry to investigate the location, abundance and phenotype of macrophages. The number of proliferating and dying ductal epithelial cells, determined by BrdU and TUNEL, was increased by 35% and 3.3-fold respectively in mammary gland transplanted with Tgfb1 null epithelium compared to wildtype epithelium (p<0.05). Abundance of F4/80+ macrophages in between Tgfb1 null epithelial cells compared to wildtype epithelial cells was increased by 50%. The number of iNOS+ and CCR7+ cells in the stroma surrounding Tgfb1 null alveolar epithelium was increased by 78% and 2-fold respectively, and dendriform MHC class II+ cells within ductal epithelium were decreased by 30%. We conclude that epithelial cell-derived TGFB1 in the mammary gland has two functions: (1) regulation of cellular turnover of epithelial cells, and (2) regulation of local macrophage phenotype. These findings shed new light on the ersity of roles of TGFB1 in the mammary gland which are likely to impact on breast cancer risk.
Publisher: Spandidos Publications
Date: 20-02-2017
Abstract: Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in high quantities by infiltrating immune cells in breast cancer. However, the functional importance of their presence within the tumour microenvironment is unclear. We have recently described a new role for peroxidases as key regulators of fibroblast and endothelial cell functionality. In the present study, we investigate for the first time, the ability of peroxidases to promote breast cancer development and progression. Using the 4T1 syngeneic murine orthotopic breast cancer model, we examined whether increased levels of peroxidases in developing mammary tumours influences primary tumour growth and metastasis. We showed that MPO and EPO stimulation increased mammary tumour growth and enhanced lung metastases, effects that were associated with reduced tumour necrosis, increased collagen deposition and neo-vascularisation within the primary tumour. In vitro, peroxidase treatment, robustly stimulated human mammary fibroblast migration and collagen type I and type VI secretion. Mechanistically, peroxidases induced the transcription of pro-tumorigenic and metastatic MMP1, MMP3 and COX-2 genes. Taken together, these findings identify peroxidases as key contributors to cancer progression by augmenting pro-tumorigenic collagen production and angiogenesis. Importantly, this identifies inflammatory peroxidases as therapeutic targets in breast cancer therapy.
Publisher: The Endocrine Society
Date: 02-2006
DOI: 10.1210/EN.2005-1189
Abstract: TGFβ1 is implicated in regulation of ovarian function and the events of early pregnancy. We have investigated the effect of null mutation in the Tgfβ1 gene on reproductive function in female mice. The reproductive capacity of TGFβ1 null mutant females was severely impaired, leading to almost complete infertility. Onset of sexual maturity was delayed, after which ovarian function was disrupted, with extended ovarian cycles, irregular ovulation, and a 40% reduction in oocytes ovulated. Serum FSH and estrogen content were normal, but TGFβ1 null mutant mice failed to display the characteristic proestrus surge in circulating LH. Ovarian hyperstimulation with exogenous gonadotropins elicited normal ovulation rates in TGFβ1 null mutant mice. After mating with wild-type stud males, serum progesterone content was reduced by 75% associated with altered ovarian expression of mRNAs encoding steroidogenic enzymes 3β-hydroxysteroid dehydrogenase-1 and P450 17 α-hydroxylase/C17–20-lyase. Embryos recovered from TGFβ1 null mutant females were developmentally arrested in the morula stage and rarely progressed to blastocysts. Attempts to rescue embryos by exogenous progesterone administration and in vitro culture were unsuccessful, and in vitro fertilization and culture experiments demonstrated that impaired development is unlikely to result from lack of maternal tract TGFβ1. We conclude that embryo arrest is due to developmental incompetence in oocytes developed in a TGFβ1-deficient follicular environment. This study demonstrates that TGFβ1 is a critical determinant of normal ovarian function, operating through regulation of LH activity and generation of oocytes competent for embryonic development and successful initiation of pregnancy.
Publisher: Wiley
Date: 26-12-2019
DOI: 10.1111/FEBS.15165
Abstract: The abundance of adipose tissue in the mammary gland obscures vision of the 3-dimensional architecture. Hitchcock et al. employed a new technique of deep tissue imaging that has enabled visualisation of dynamic interactions between mammary gland epithelial and immune cells with unprecedented 3-dimensional clarity. Deep imaging will help further our understanding of the complex biological interactions that underpin both normal mammary gland development and the susceptibility of this tissue to cancer. This knowledge will assist the development of much-needed prevention strategies to reduce the incidence of breast cancer. Comment on: 0.1111/febs.15126.
Publisher: Oxford University Press (OUP)
Date: 10-2008
DOI: 10.1095/BIOLREPROD.107.067272
Abstract: The cytokine-transforming growth factor beta1 (TGFB1) is implicated in development of the mammary gland through regulation of epithelial cell proliferation and differentiation during puberty and pregnancy. We compared mammary gland morphogenesis in virgin Tgfb1(+/+), Tgfb1(+/-), and Tgfb1(-/-) mice and transplanted Tgfb1(+/+) and Tgfb1(-/-) epithelium to determine the impact of TGFB1 deficiency on development. When mammary gland tissue was evaluated relative to the timing of puberty, invasion through the mammary fat pad of the ductal epithelium progressed similarly, irrespective of genotype, albeit fewer terminal end buds were observed in mammary glands from Tgfb1(-/-) mice. The terminal end buds appeared to be normal morphologically, and a comparable amount of epithelial proliferation was evident. When transplanted into wild-type recipients, however, Tgfb1(-/-) epithelium showed accelerated invasion compared with Tgfb1(+/+) epithelium. This suggests that the normal rate of ductal extension in Tgfb1(-/-) null mutant mice is the net result of impaired endocrine or paracrine support acting to limit the consequences of unrestrained epithelial growth. By adulthood, mammary glands in cycling virgin Tgfb1(-/-) mice were morphologically similar to those in Tgfb1(+/+) and Tgfb1(+/-) animals, with a normal branching pattern, and the tissue differentiated into early alveolar structures in the diestrous phase of the ovarian cycle. Transplanted mammary gland epithelium showed a similar extent of ductal branching and evidence of secretory differentiation of luminal cells in pregnancy. These results reveal two opposing actions of TGFB1 during pubertal mammary gland morphogenesis: autocrine inhibition of epithelial ductal growth, and endocrine or paracrine stimulation of epithelial ductal growth.
Publisher: The Endocrine Society
Date: 08-2007
DOI: 10.1210/EN.2006-1759
Abstract: TGFbeta1 is a multifunctional cytokine implicated in gonad and secondary sex organ development, steroidogenesis, and spermatogenesis. To determine the physiological requirement for TGFbeta1 in male reproduction, Tgfb1 null mutant mice on a Prkdc(scid) immunodeficient background were studied. TGFbeta1-deficient males did not deposit sperm or induce pseudopregnancy in females, despite an intact reproductive tract with morphologically normal penis, seminal vesicles, and testes. Serum and intratesticular testosterone and serum androstenedione were severely diminished in TGFbeta1-deficient males. Testosterone deficiency was secondary to disrupted pituitary gonadotropin secretion because serum LH and to a lesser extent serum FSH were reduced, and exogenous LH replacement with human chorionic gonadotropin (hCG) induced serum testosterone to control levels. In the majority of TGFbeta1-deficient males, spermatogenesis was normal and sperm were developmentally competent as assessed by in vitro fertilization. Analysis of sexual behavior revealed that although TGFbeta1 null males showed avid interest in females and engaged in mounting activity, intromission was infrequent and brief, and ejaculation was not attained. Administration of testosterone to adult males, even after neonatal androgenization, was ineffective in restoring sexual function however, erectile reflexes and ejaculation could be induced by electrical stimulation. These studies demonstrate the profound effect of genetic deficiency in TGFbeta1 on male fertility, implicating this cytokine in essential roles in the hypothalamic-pituitary-gonadal axis and in testosterone-independent regulation of mating competence.
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 13-06-2014
DOI: 10.1007/S10911-014-9319-7
Abstract: Dynamic interactions between the hormone responsive mammary gland epithelium and surrounding stromal macrophage populations are critical for normal development and function of the mammary gland. Macrophages are versatile cells capable of erse roles in mammary gland development and maintenance of homeostasis, and their function is highly dependent on signals within the local cytokine microenvironment. The mammary epithelium secretes a number of cytokines, including colony stimulating factor 1 (CSF1), transforming growth factor beta 1 (TGFB1), and chemokine ligand 2 (CCL2) that affect the abundance, phenotype and function of macrophages. However, aberrations in these interactions have been found to increase the risk of tumour formation, and utilisation of stromal macrophage support by tumours can increase the invasive and metastatic potential of the cancer. Studies utilising genetically modified mouse models have shed light on the significance of epithelial cell-macrophage crosstalk, and the cytokines that mediate this communication, in mammary gland development and tumourigenesis. This article reviews the current status of our understanding of the roles of epithelial cell-derived cytokines in mammary gland development and cancer, with a focus on the crosstalk between epithelial cells and the local macrophage population.
Publisher: MDPI AG
Date: 03-03-2020
DOI: 10.3390/JCM9030681
Abstract: Breast density, also known as mammographic density, refers to white and bright regions on a mammogram. Breast density can only be assessed by mammogram and is not related to how breasts look or feel. Therefore, women will only know their breast density if they are notified by the radiologist when they have a mammogram. Breast density affects a woman’s breast cancer risk and the sensitivity of a screening mammogram to detect cancer. Currently, the position of BreastScreen Australia and the Royal Australian and New Zealand College of Radiologists is to not notify women if they have dense breasts. However, patient advocacy organisations are lobbying for policy change. Whether or not to notify women of their breast density is a complex issue and can be framed within the context of both public health ethics and clinical ethics. Central ethical themes associated with breast density notification are equitable care, patient autonomy in decision-making, trust in health professionals, duty of care by the physician, and uncertainties around evidence relating to measurement and clinical management pathways for women with dense breasts. Legal guidance on this issue must be gained from broad legal principles found in the law of negligence and the test of materiality. We conclude a rigid legal framework for breast density notification in Australia would not be appropriate. Instead, a policy framework should be developed through engagement with all stakeholders to understand and take account of multiple perspectives and the values at stake.
Publisher: Wiley
Date: 13-09-2016
DOI: 10.1002/CBIN.10675
Abstract: Women with high mammographic density (MD) are at increased risk of breast cancer (BC) after adjustment for age and body mass index. We have developed a murine biochamber model in which both high MD (HMD) and low MD (LMD) tissue can be propagated. Here, we tested whether cells isolated by collagenase digestion and fluorescence-activated cell sorting (FACS) from normal breast can be reconstituted in our biochamber model, which would allow cell-specific manipulations to be tested. Fresh breast tissue was collected from women (n = 7) undergoing prophylactic mastectomy. The tissue underwent collagenase digestion overnight and, in some cases, additional FACS enrichment to obtain mature epithelial, luminal progenitor, mammary stem, and stromal cells. Cells were then transferred bilaterally into biochambers in SCID mice (n = 5-7) and incubated for 6 weeks, before harvesting for histological analyses, and immunohistochemical staining for cytokeratins (CK), vimentin, Ki-67, murine macrophages, and Cleaved Caspase-3. Biochambers inoculated with single cells after collagenase digestion or with flow cytometry contained glandular structures of human origin (human vimentin-positive), which expressed CK-14 and pan-CK, and were proliferating (Ki-67-positive). Glandular structures from the digested tissues were smaller than those in chambers seeded with finely chopped intact mammary tissue. Mouse macrophage infiltration was higher in the chambers arising from digested tissues. Pooled single cells and FACS fractionated cells were viable in the murine biochambers and formed proliferating glandular organoids of human origin. This is among the first report to demonstrate the success of formed human glandular organoids from isolated primary mammary cells in the murine biochamber model.
Publisher: Wiley
Date: 25-09-2002
DOI: 10.1002/BIES.10155
Abstract: Members of the transforming growth factor beta (TGFbeta) family are pleiotropic cytokines with key roles in tissue morphogenesis and growth. TGFbeta1, TGFbeta2 and TGFbeta3 are abundant in mammalian reproductive tissues, where development and cyclic remodelling continue in post-natal and adult life. Potential roles for TGFbeta have been identified in gonad and secondary sex organ development, spermatogenesis and ovarian function, immunoregulation of pregnancy, embryo implantation and placental development. However, better tools must now be employed to map more precisely essential functions and the regulatory networks governing their activity. Gene ablation and transgenic models are expected to provide novel insights into distinct physiological activities for each TGFbeta isoform in normal reproductive function and reproductive pathologies. It is also necessary to consider the mechanisms controlling TGFbeta activation from latent precursor forms, and receptor and binding protein expression. Smad intracellular signalling circuitry and modulation by environmental stimuli through cross-talk with other signal transduction pathways will further constrain TGFbeta action. This review examines existing evidence for TGFbeta1, TGFbeta2 and TGFbeta3 regulation of male and female reproductive biology, and highlights prospects for future research.
Publisher: Frontiers Media SA
Date: 26-12-2016
Publisher: MDPI AG
Date: 17-04-2023
DOI: 10.3390/IJMS24087385
Abstract: CCL2 is an inflammatory cytokine that regulates macrophage activity and is implicated in increased mammographic density and early breast tumorigenesis. The role of CCL2 in mediating stromal interactions that contribute to breast tumorigenesis has yet to be fully elucidated. THP-1-derived macrophages and mammary fibroblasts were co-cultured for 72 h. Fibroblasts and macrophages were analysed for phenotype, expression of inflammatory and ECM-regulatory genes and collagen production. Mice overexpressing CCL2 in the mammary glands were analysed for global gene expression by RNAseq at 12 weeks of age. These mice were cross-bred with PyMT mammary tumour mice to examine the role of CCL2 in tumorigenesis. The co-culture of macrophages with fibroblasts resulted in macrophage polarization towards an M2 phenotype, and upregulated expression of CCL2 and other genes associated with inflammation and ECM remodelling. CCL2 increased the production of insoluble collagen by fibroblasts. A global gene expression analysis of CCL2 overexpressing mice revealed that CCL2 upregulates cancer-associated gene pathways and downregulates fatty acid metabolism gene pathways. In the PyMT mammary tumour model, CCL2 overexpressing mice exhibited increased macrophage infiltration and early tumorigenesis. Interactions between macrophages and fibroblasts regulated by CCL2 can promote an environment that may increase breast cancer risk, leading to enhanced early tumorigenesis.
Publisher: Wiley
Date: 10-08-2017
DOI: 10.1002/CAM4.1115
Publisher: Wiley
Date: 28-11-2022
DOI: 10.1111/PPE.12824
Abstract: Mastitis is a common and distressing maternal postpartum condition, but the relationship between mastitis timing and antibiotic treatment and breastfeeding outcomes and postnatal mental health is unclear. To describe the incidence of mastitis and treatment with antibiotics in first 6 months postpartum, and to investigate the impact of mastitis timing and antibiotic treatment on breastfeeding practices and postnatal mental health. This study is based on 79,985 mother‐infant dyads in the Norwegian Mother, Father and Child Cohort Study (MoBa). Women were classified according to self‐reported mastitis within first month (‘early’) or 1–6 months (‘later’) postpartum and antibiotic treatment. Breastfeeding outcomes included predominant or any breastfeeding and abrupt breastfeeding cessation until 6 months postpartum. Maternal mental health was assessed by self‐report at 6 months postpartum. The incidence of mastitis was 18.8%, with 36.8% reporting treatment with antibiotics. Women reporting early mastitis were less likely to report predominant breastfeeding (adjustedd relative risk [aRR] 0.92, 95% confidence interval [CI] 0.86, 0.99) and any breastfeeding for 6 months (aRR 0.97, 95% CI 0.96, 0.98) than women who did not report mastitis, and more likely to report abrupt breastfeeding cessation (aRR 1.37, 95% CI 1.23, 1.53). Late‐onset mastitis was not associated with poorer breastfeeding outcomes. Among women reporting mastitis, the risk of abrupt breastfeeding cessation was higher in those also reporting antibiotic use. Mastitis was associated with an increased risk of mental health problems postpartum which was highest among those reporting no antibiotic use (aRR 1.29, 95% CI 1.18, 1.41), in contrast to those also reporting antibiotic use (aRR 1.08, 95% CI 0.96, 1.22). Lactational mastitis and its associated treatment with antibiotics are common. Early ( month postpartum) mastitis appears to be a modest risk factor for suboptimal breastfeeding outcomes. In addition, mastitis is associated with poorer mental health.
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2019
DOI: 10.1158/0008-5472.CAN-19-1698
Abstract: There is increasing interest in the role of the gut microbiome in health and disease, and a number of observational and in vitro studies have suggested it may play a role in breast cancer development and progression. Buchta Rosean and colleagues present the first functional evidence that a preexisting disturbance in the gut microbiome leads to increased breast cancer cell metastasis in a mouse model. This discovery places the gut microbiome as a new player in breast cancer metastasis however, further studies are required to determine the relevance of the findings in this mouse model to human disease. A better understanding of the relationship between the bacterial ecosystem of the gut and progression of breast cancer has enormous potential for improving treatment outcomes for patients with breast cancer. See related article by Buchta Rosean et al., p. 3662
Publisher: Springer Science and Business Media LLC
Date: 24-03-2021
DOI: 10.1186/S13058-021-01417-8
Abstract: Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. TGFB1 also plays roles in tumour development and progression, and its increased expression is associated with an increased breast cancer risk. Macrophages are key target cells for TGFB1 action, also playing crucial roles in tumourigenesis. However, the precise role of TGFB-regulated macrophages in the mammary gland is unclear. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice. A transgenic mouse model was generated, wherein a dominant negative TGFB receptor is activated in macrophages, in turn attenuating the TGFB signalling pathway specifically in the macrophage population. The mammary glands were assessed for morphological changes through wholemount and H& E analysis, and the abundance and phenotype of macrophages were analysed through immunohistochemistry. Another cohort of mice received carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), and tumour development was monitored weekly. Human non-neoplastic breast tissue was also immunohistochemically assessed for latent TGFB1 and macrophage marker CD68. Attenuation of TGFB signalling resulted in an increase in the percentage of alveolar epithelium in the mammary gland at dioestrus and an increase in macrophage abundance. The phenotype of macrophages was also altered, with inflammatory macrophage markers iNOS and CCR7 increased by 110% and 40%, respectively. A significant decrease in DMBA-induced mammary tumour incidence and prolonged tumour-free survival in mice with attenuated TGFB signalling were observed. In human non-neoplastic breast tissue, there was a significant inverse relationship between latent TGFB1 protein and CD68-positive macrophages. TGFB acts on macrophage populations in the mammary gland to reduce their abundance and d en the inflammatory phenotype. TGFB signalling in macrophages increases mammary cancer susceptibility potentially through suppression of immune surveillance activities of macrophages.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.AJPATH.2011.11.013
Abstract: Transforming growth factor-β1 (TGFB1) is a multifunctional cytokine that is abundant in both endometriotic lesions and the peritoneal fluid in women with endometriosis. However, the role of TGFB1 in the development of endometriosis is as yet undefined. In the present study, we investigated the physiologic function of TGFB1 in endometriotic lesion development, using Tgfb1-null mutant mice on a background of severe combined immunodeficiency. Xenotransplantation of human eutopic endometrial tissue resulted in development of endometriosis-like lesions in 63% of ovariectomized estrogen-supplemented Tgfb1-null mutant mice and in 68% of wild-type control mice. Median lesion weight was reduced by 11-fold in Tgfb1-null mice compared with wild-type control mice, and the fraction of glandular epithelium in lesions from Tgfb1-null mice was reduced by 32% compared with that in control mice. In lesions from Tgfb1-null mice, the relative abundance of both macrophages and α-smooth muscle actin-positive myofibroblasts was reduced by 66% and 47%, respectively. Deficiency of TGFB1 neither altered the percentage of proliferating cells in the epithelial or stromal compartments of the lesions nor affected blood vessel density or vessel size. Observation of this study indicates that host-derived TGFB1 deficiency suppresses endometriotic lesion development and provides proof of principle that targeting TGFB1 signaling pathways in cells that support the survival of ectopic endometrium may be an effective therapeutic approach in women with endometriosis.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2015
Publisher: Spandidos Publications
Date: 24-06-2020
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JRI.2014.07.002
Abstract: The mammary gland is a unique organ that undergoes hormone-driven developmental changes over the course of the ovarian cycle during adult life. Macrophages play a role in regulating cellular turnover in the mammary gland and may affect cancer susceptibility. However, the immune microenvironment that regulates macrophage function has not been described. Hormonal regulation of the cytokine microenvironment across the ovarian cycle was explored using microbead multiplex assay for 15 cytokines in mammary glands from C57Bl/6 mice at different stages of the oestrous cycle, and in ovariectomised mice administered oestradiol and progesterone. The cytokines that were found to fluctuate over the course of the oestrous cycle were colony-stimulating factor (CSF)1, CSF2, interferon gamma (IFNG) and tumour necrosis factor alpha (TNFA), all of which were significantly elevated at oestrus compared with other phases. The concentration of serum progesterone during the oestrus phase negatively correlated with the abundance of cytokines CSF3, IL12p40, IFNG and leukaemia inhibitory factor (LIF). In ovariectomised mice, exogenous oestradiol administration increased mammary gland CSF1, CSF2, IFNG and LIF, compared with ovariectomised control mice. Progesterone administration together with oestradiol resulted in reduced CSF1, CSF3 and IFNG compared with oestradiol administration alone. This study suggests that the cytokine microenvironment in the mammary gland at the oestrus phase of the ovarian cycle is relatively pro-inflammatory compared with other stages of the cycle, and that the oestradiol-induced cytokine microenvironment is significantly attenuated by progesterone. A continuously fluctuating cytokine microenvironment in the mammary gland presumably regulates the phenotypes of resident leukocytes and may affect mammary gland cancer susceptibility.
Publisher: The Company of Biologists
Date: 15-12-2010
DOI: 10.1242/DEV.059261
Abstract: Each ovarian cycle, the mammary gland epithelium rotates through a sequence of hormonally regulated cell proliferation, differentiation and apoptosis. These studies investigate the role of macrophages in this cellular turnover. Macrophage populations and their spatial distribution were found to fluctuate across the cycle. The number of macrophages was highest at diestrus, and the greatest number of macrophages in direct contact with epithelial cells occurred at proestrus. The physiological necessity of macrophages in mammary gland morphogenesis during the estrous cycle was demonstrated in Cd11b-Dtr transgenic mice. Ovariectomised mice were treated with estradiol and progesterone to stimulate alveolar development, and with the progesterone receptor antagonist mifepristone to induce regression of the newly formed alveolar buds. Macrophage depletion during alveolar development resulted in a reduction in both ductal epithelial cell proliferation and the number of alveolar buds. Macrophage depletion during alveolar regression resulted in an increased number of branch points and an accumulation of TUNEL-positive cells. These studies show that macrophages have two roles in the cellular turnover of epithelial cells in the cycling mammary gland following ovulation, they promote the development of alveolar buds in preparation for possible pregnancy, and they remodel the tissue back to its basic architecture in preparation for a new estrous cycle.
Publisher: Spandidos Publications
Date: 27-05-2014
Publisher: Wiley
Date: 06-10-2006
DOI: 10.1002/DVDY.20972
Abstract: Development of the ductal network in the mammary gland is dependent in part on the presence of macrophages. Here we utilize multi-photon microscopy and second harmonic generation to describe terminal end bud 3-dimensional structure and the organization of the surrounding collagen matrix. We have applied this approach to analyze the effect of macrophage deficiency on terminal end bud structure and collagen organization, using mice homozygous for a null mutation in the colony stimulating factor-1 gene (Csf1op/Csf1op). Primary terminal end buds have an oblong shape, with long collagen I fibers close to the neck of the terminal end bud and radiating upwards in the direction of growth. Around the terminal end buds, the amount of total collagen I detected by antibody staining was not affected by macrophage deficiency. However the amount of collagen I organized into long fibers, detected by second harmonic generation signal, was reduced in Csf1op/Csf1op mice. Macrophage deficiency also caused terminal end buds to be rounder and shorter. These studies reveal a role for macrophages in collagen fibrillogenesis and in organization of the structure of terminal end buds.
Publisher: Oxford University Press (OUP)
Date: 09-2013
DOI: 10.1095/BIOLREPROD.113.109561
Abstract: The mammary gland undergoes development and regression over the course of the ovarian cycle under the regulation of ovarian hormones. Macrophages are implicated as local mediators of this tissue remodeling and may also affect immune surveillance and tumor incidence. To investigate cycle-related changes in macrophage phenotype, mammary gland cells from naturally cycling Cfms-Gfp mice recovered at estrus, metestrus, diestrus, and proestrus were analyzed by flow cytometry. Macrophage expression of MHCII was highest in the proestrus phase, with a 1.6-fold increase compared to the metestrus phase. Similarly, macrophage expression of CD204 was 1.9-fold higher at proestrus compared to estrus. Conversely, macrophage expression of NKG2D was increased at metestrus and diestrus by 7-fold and 5-fold, respectively, compared to estrus. To investigate hormonal regulation of macrophage phenotype, an ovariectomy and hormone replacement model was utilized. Ovariectomized mice were stimulated with exogenous estradiol and progesterone to induce early alveolar development, then given progesterone receptor antagonist RU486 to elicit alveolar bud regression. Progesterone and estradiol in combination reduced macrophage expression of MHCII and CD204 by 5-fold and 3-fold, respectively, and increased macrophage expression of NKG2D by 4-fold. Administration of RU486, following estradiol and progesterone, reversed the macrophage phenotype. These results reveal an essential requirement for ovarian hormones in regulating macrophage phenotype in the mammary gland and indicate that progesterone is particularly critical for controlling macrophage antigen presentation and immune surveillance capacity.
Publisher: Elsevier BV
Date: 02-2014
Publisher: The Endocrine Society
Date: 16-08-2011
DOI: 10.1210/EN.2011-1133
Abstract: There is emerging evidence that androgens inhibit proliferation of normal and malignant breast epithelial cells, but the actions of androgens in normal mammary gland morphogenesis are not well understood. In this study, we investigated whether development of the murine mammary gland could be altered by stimulating or suppressing androgen receptor (AR) signaling in vivo. Intact virgin female mice aged 5 wk (midpuberty) or 12 wk (postpuberty) were implanted with slow-release pellets containing either placebo, 5α-dihydrotestosterone (1.5 mg) or the AR antagonist flutamide (60 mg). Treatment with 5α-dihydrotestosterone from midpuberty to 12 wk of age-retarded ductal extension by 40% (P = 0.007), but treatment from 12-21 wk had no significant effect on gland morphology. In contrast, inhibition of AR signaling with flutamide from midpuberty had no effect on the mammary gland, but flutamide treatment from 12-21 wk increased ductal branching (P = 0.004) and proliferation (P = 0.03) of breast epithelial cells. The increased proliferation in flutamide-treated mice was not correlated with serum estradiol levels or estrogen receptor-α (ERα) expression. In control mice, the frequency and intensity of AR immunostaining in mammary epithelial cells was significantly increased in the 12- to 21-wk treatment group compared with the 5- to 12-wk group (P < 0.001). In contrast, no change in ERα occurred, resulting in a marked increase in the AR to ERα ratio from 0.56 (±0.12) to 1.47 (±0.10). Our findings indicate that androgen signaling influences development and structure of the adult mammary gland and that homeostasis between estrogen and androgen signaling in mature glands is critical to constrain the proliferative effects of estradiol.
Location: No location found
Location: United States of America
No related grants have been discovered for Wendy Ingman.