New insights into the role of androgen and oestrogen receptors in molecular apocrine breast tumours.
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ABSTRACT:
SUBMITTER: Iggo RD
PROVIDER: S-EPMC3326548 | biostudies-literature | 2011
REPOSITORIES: biostudies-literature
Publications
New insights into the role of androgen and oestrogen receptors in molecular apocrine breast tumours.
Breast cancer research : BCR 20111208 6
Two recent studies on a rare androgen-dependent form of breast cancer have shed light on the biology of luminal tumours and reinforced the view that interfering with androgen signalling may have a place in the therapy of some forms of breast cancer. ...[more]
Similar Datasets
Project description:Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumours were recently identified as an additional subgroup, characterised as oestrogen receptor negative and androgen receptor positive (ER- AR+), but with an expression profile resembling ER+ luminal breast cancer. One possible explanation for the apparent incongruity is that ER gene expression programmes could be recapitulated by AR. Using a cell line model of ER- AR+ molecular apocrine tumours (termed MDA-MB-453 cells), we map global AR binding events and find a binding profile that is similar to ER binding in breast cancer cells. We find that AR binding is a near-perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a nuclear receptor. AR functionality is dependent on FoxA1, since silencing of FoxA1 inhibits AR binding, expression of the majority of the molecular apocrine gene signature and growth cell growth. These findings show that AR binds and regulates ER cis-regulatory elements in molecular apocrine tumours, resulting in a transcriptional programme reminiscent of ER-mediated transcription in luminal breast cancers.
| S-EPMC3160190 | biostudies-literature
Project description:BackgroundThe most striking feature of molecular apocrine breast cancer (MABC) is the expression of androgen receptor (AR). We report here the mechanism of the AR in regulating the behavior of MABC.MethodsThe MABC cell line, MDA-MB-453, and the nonMABC cell line, MCF7, were used in this study. The effect of dihydrotestosterone (DHT) and heat shock protein 27 (HSP27) on cell proliferation was quantified using the cell counter kit-8 (CCK8) and clonogenic assays in vitro and by a xenograft tumor model in vivo. The expression of the AR and HSP27 was analyzed using western blot, qPCR, and immunofluorescence assays. Complexes of the AR and HSP27 were detected by co-immunoprecipitation (Co-IP).ResultsIn MDA-MB-453 cells, DHT promoted cell proliferation and stimulated AR and HSP27 translocation from the cytoplasm to the nucleus, whereas, it inhibited MCF7 cell growth, and only the AR translocated into the nucleus. HSP27 knock-down decreased the proliferative ability of MDA-MB-453 cells, which could be rescued by DHT, while HSP27 and DHT had synergistic effects on MCF7 cells. HSP27 phosphorylation was a prerequisite for AR translocation into the nucleus, especially phosphorylation on serine 82. In addition, DHT stimulated the tumorigenic and metastatic capacities of MDA-MB-453 cells, while HSP27 knock-down decreased the rate of tumor formation and induced apoptosis in cells.ConclusionsThe results suggest that HSP27 assists the AR in regulating the malignant behavior of MABC, and these findings might be helpful in the treatment of MABC.
| S-EPMC5921986 | biostudies-literature
Project description:Pathway discovery from gene expression data can provide important insight into the relationship between signaling networks and cancer biology. Oncogenic signaling pathways are commonly inferred by comparison with signatures derived from cell lines. We use the Molecular Apocrine subtype of breast cancer to demonstrate our ability to infer pathways directly from patients' gene expression data with pattern analysis algorithms.We combine data from two studies that propose the existence of the Molecular Apocrine phenotype. We use quantile normalization and XPN to minimize institutional bias in the data. We use hierarchical clustering, principal components analysis, and comparison of gene signatures derived from Significance Analysis of Microarrays to establish the existence of the Molecular Apocrine subtype and the equivalence of its molecular phenotype across both institutions. Statistical significance was computed using the Fasano & Franceschini test for separation of principal components and the hypergeometric probability formula for significance of overlap in gene signatures. We perform pathway analysis using LeFEminer and Backward Chaining Rule Induction to identify a signaling network that differentiates the subset. We identify a larger cohort of samples in the public domain, and use Gene Shaving and Robust Bayesian Network Analysis to detect pathways that interact with the defining signal.We demonstrate that the two separately introduced ER- breast cancer subsets represent the same tumor type, called Molecular Apocrine breast cancer. LeFEminer and Backward Chaining Rule Induction support a role for AR signaling as a pathway that differentiates this subset from others. Gene Shaving and Robust Bayesian Network Analysis detect interactions between the AR pathway, EGFR trafficking signals, and ErbB2.We propose criteria for meta-analysis that are able to demonstrate statistical significance in establishing molecular equivalence of subsets across institutions. Data mining strategies used here provide an alternative method to comparison with cell lines for discovering seminal pathways and interactions between signaling networks. Analysis of Molecular Apocrine breast cancer implies that therapies targeting AR might be hampered if interactions with ErbB family members are not addressed.
| S-EPMC2753593 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-07-18 | GSE70163 | GEO
Project description:The majority of breast cancer subtypes express androgen receptor (AR) in addition to estrogen receptor a (ERa). Depending on the breast cancer subtype androgen signaling has either stimulatory or inhibitory roles in breast cancer cell growth. We have mapped AR cistrome in ERa negative human molecular apocrine breast cancer MDA-MB453 cells and analyzed it in relation to the androgen-regulated transcriptome in the same cells. We have also examined the effect of silencing of the coregulator SUMO ligase PIAS1 on the androgen-regulated transcriptome and AR cistrome in MDA-MB453 cells. Our results show that the MDA-MB453 cells share with VCaP prostate cancer cells a core AR cistrome and target gene signature linked to cancer cell growth and that PIAS1 acts as an AR target gene-selective coregulator in MDA-MB453 cells.
2016-07-18 | GSE70161 | GEO
Project description:Genomic profiling was performed on explants of late proliferative phase human endometrium after 24-h treatment with progesterone (P) or oestradiol and progesterone (17beta-E(2)+P) and on explants of menstrual phase endometrium treated with 17beta-E(2)+P. Gene expression was validated with real-time PCR in the samples used for the arrays, in endometrium collected from early and mid-secretory phase endometrium, and in additional experiments performed on new samples collected in the menstrual and late proliferative phase. The results show that late proliferative phase human endometrium is more responsive to progestins than menstrual phase endometrium, that the expression of several genes associated with embryo implantation (i.e. thrombomodulin, monoamine oxidase A, SPARC-like 1) can be induced by P in vitro, and that genes that are fully dependent on the continuous presence of 17beta-E(2) during P exposure can be distinguished from those that are P-dependent to a lesser extent. Therefore, 17beta-E(2) selectively primes implantation-related genes for the effects of P.
| S-EPMC2778656 | biostudies-literature
Project description:Measuring the effect of silencing of NRIP1 in an endometrial tumour cell line on gene expression.
2011-10-31 | E-MTAB-820 | biostudies-arrayexpress
Project description:Carcinomas with apocrine differentiation (CAD) of the breast are rare tumours typically presenting high immunohistochemical expression of androgen receptor (AR) which is a target molecule for personalised therapy. To date, no studies have evaluated the genetic changes that are associated with AR immunohistochemical expression in CADs. The present work aims to characterise AR status in CADs. Twenty CAD tumours were studied with immunohistochemistry, in situ fluorescence hybridization and DNA methylation analysis, to evaluate AR expression and its regulator status. All tumours demonstrated high AR immunohistochemical expression, with over 95% of the neoplastic cells showing AR positivity in 19/20 cases. CADs showed AR gene copy loss in a percentage of neoplastic cells ranging from 5 to 84% (mean 48.93%). AR regulator genes, including the MAGE family, UXT and FLNA, presented variable methylation levels, but were mainly hypomethylated and therefore all transcriptionally active. The results of this study indicate that CADs present AR monosomy, paralleled by higher transcriptional activity of the gene with potential to influence response to AR deprivation therapy.
| S-EPMC8364532 | biostudies-literature
Project description:Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation.To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer.Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point.In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR)=0.34; 95% confidence interval (CI)=0.14-0.81; P=0.015), whereas the opposite was seen in the AR- group (HR=2.92; 95% CI=1.16-7.31; P=0.022). Interaction test was significant P<0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR=0.12; 95% CI=0.014-0.95 P=0.044), whereas patients with AR- tumours had worse outcome when treated with tamoxifen (HR=3.98; 95% CI=1.32-12.03; P=0.014). Interaction test was significant P=0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression.AR can predict tamoxifen treatment benefit in patients with ER- tumours and triple-negative breast cancer.
| S-EPMC4742586 | biostudies-literature
Project description:BACKGROUND:Androgen Receptor (AR) is an essential transcription factor for the development of secondary sex characteristics, spermatogenesis and carcinogenesis. Recently AR has been implicated in the development and progression of breast and prostate cancers. Although some of the functions of the AR are known but the mechanistic details of these divergent processes are still not clear. Therefore understanding the regulatory mechanisms of the functioning of the AR in ER-/AR+ breast cancer will provide many novel targets for the purpose of therapeutic intervention. METHODS/RESULTS:Using bioinformatics tools, we have identified 75 AR targets having prominent roles in cell cycle, apoptosis and metabolism. Herein, we validated 10 genes as AR targets by studying the regulation of these genes in MDA-MB-453 cell line on stimulation by androgens like 5?-dihydrotestosterone (DHT), using RT-qPCR and ChIP assay. It was observed that all the identified genes involved in cell cycle except MAD1L1 were found to be up regulated whereas expression of apoptosis related genes was decreased in response to DHT treatment. We performed an exhaustive, rigid-body docking between individual ARE and DNA binding domain (DBD) of the AR protein and it was found that novel residues K567, K588, K591 and R592 are involved in the process of DNA binding. To verify these specific DNA-protein interactions electrostatic energy term calculations for each residue was determined using the linearized Poisson-Boltzmann equation. Our experimental data showed that treatment of breast cancer cells with DHT promotes cell proliferation and decreases apoptosis. It was observed that bicalutamide treatment was able to reverse the effect of DHT. CONCLUSION:Taken together, our results provide new insights into the mechanism by which AR promotes breast cancer progression. Moreover our work proposes to use bicalutamide along with taxanes as novel therapy for the treatment of TNBCs, which are positive for downstream AR signalling.
| S-EPMC4364071 | biostudies-literature