title: Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo.
abstract: OBJECTIVE
  Medroxyprogesterone acetate (MPA), a component of combined estrogen-progestin therapy (EPT), has been associated with increased breast cancer risk in EPT users. MPA can bind to the androgen receptor (AR), and AR signaling inhibits cell growth in breast tissues. Therefore, the aim of this study was to investigate the potential of MPA to disrupt AR signaling in an ex vivo culture model of normal human breast tissue.
  
  
  METHODS
  Histologically normal breast tissues from women undergoing breast surgical operation were cultured in the presence or in the absence of the native AR ligand 5α-dihydrotestosterone (DHT), MPA, or the AR antagonist bicalutamide. Ki67, bromodeoxyuridine, B-cell CLL/lymphoma 2 (BCL2), AR, estrogen receptor α, and progesterone receptor were detected by immunohistochemistry.
  
  
  RESULTS
  DHT inhibited the proliferation of breast epithelial cells in an AR-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. These hormonal responses were not commonly observed in cultured tissues from premenopausal women. In tissues from postmenopausal women, DHT either induced or repressed BCL2 expression, and the antiandrogenic effect of MPA on BCL2 was variable. MPA significantly opposed the positive effect of DHT on AR stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels.
  
  
  CONCLUSIONS
  In a subset of postmenopausal women, MPA exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT.
authors.affiliation: From the 1Dame Roma Mitchell Cancer Research Laboratories, Hanson Institute, Discipline of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia; and 2Emphron Informatics, Toowong, QLD, Australia.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Ochnik
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Moore
authors.forename: Tanja
authors.initials: T
authors.lastname: Jankovic-Karasoulos
authors.forename: Tina
authors.initials: T
authors.lastname: Bianco-Miotto
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Ryan
authors.forename: Mervyn R
authors.initials: MR
authors.lastname: Thomas
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Birrell
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Theresa E
authors.initials: TE
authors.lastname: Hickey
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001940:Breast / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects*; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D017698:Postmenopause; D017697:Premenopause / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; C053541:bicalutamide; D017258:Medroxyprogesterone Acetate; D001973:Bromodeoxyuridine