title: Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer.
abstract: OBJECTIVE
  Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells.
  
  
  METHODS
  MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide.
  
  
  RESULTS
  We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively.
  
  
  CONCLUSIONS
  Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.
authors.forename: Aiyu
authors.initials: A
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xu
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Yin
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Guan
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism*; D014105:Tosyl Compounds / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072160:Tumor Protein p73 / Q000235:genetics* / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000813:Anilides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009570:Nitriles; D011944:Receptors, Androgen; C000606460:TP73 protein, human; D014105:Tosyl Compounds; D000072160:Tumor Protein p73; D013196:Dihydrotestosterone; C053541:bicalutamide