Androgen And AR Contribute To Breast Cancer Development And Metastasis:An Insight Of Mechanisms

Though normally thought to be a male hormone,androgen could also be detected in women's circulation at a biological functional level.Androgen has been reported to be associated with breast cancer risk,especially in postmenopausal women.However,as the receptor of androgen,androgen receptor(AR)is implicated as a good prognostic factor in breast cancer,associating with longer relapse-free,metastasis-free and overall survival,smaller tumor size,lower histological grade,a favorable response to chemotherapy and hormonal therapy.There have been indications that androgen contributes to carcinogenesis by converting into estrogenic hormones.Nevertheless,no clinical statistic research or experimental research have been carried out to prove this theory right or wrong.In this report,we provide evidence that the androgen hormone dihydrotestosterone(DHT)is able to induce the epithelial-to-mesenchymal transition(EMT)in breast cancer cells in an AR-dependent and ER-independent manner.We showed that DHT could induce EMT not only in ER positive and AR positive MCF-7 cells but also in AR positive and ER negative T47 D cells.We also proved that DHT could evaluate the migration and invasion ability of breast cancer cells via inducing EMT.We show that the EMT program initiated by DHT is dependent on the demethylation activity of lysine-specific demethylase 1(LSD1)through regulating the expression of target genes E-cadherin and vimentin.We analyzed and found AR response elements(AREs)on E-cadherin and vimentin promoters.Chromatin immunoprecipitation analysis indicated AR and LSD1 formed a complex and bound to both E-cadherin and vimentin promoter.Specifically,the DHT-mediated AR and LSD1 enrichment leads to the decreased H3K4me2(an active chromatin marker)at the E-cadherin promoter and thus represses E-cadherin promoter activity,whereas it strongly reduces H3K9me2(a repressive chromatin signature)at the vimentin promoter and therefore activates vimentin promoter to facilitate transcription.We also demonstrate with mammary fat pat injection in situ metastasis research model in nude mice model that DHT promotes metastasis in vivo,and AR and LSD1 are crucial in this process.Significantly,we establish that higher levels of nuclear AR and LSD1 are associated with higher cancer grade and worse prognostic outcomes.In conclusion,data from this study map an “androgen—AR/LSD1—target gene” pathway in breast cancer carcinogenesis.This model implicates the importance of hormonal balance in women,and points to the potential clinical value of evaluating serum androgen and AR levels in prediction and diagnosis of breast cancer in women.