Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo

Aleksandra M. Ochnik, Nicole L. Moore, Tanja Jankovic-Karasoulos, Tina Bianco-Miotto, Natalie K. Ryan, Mervyn R. Thomas, Stephen N. Birrell, Lisa M. Butler, Wayne D. Tilley, Theresa E. Hickey

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)79-88
Number of pages10
JournalMenopause
Volume21
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

Keywords

  • 5α-Dihydrotestosterone
  • Androgen receptor
  • breast cancer
  • Estrogen-progestin therapy
  • Medroxyprogesterone acetate
  • Menopause

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    Ochnik, A. M., Moore, N. L., Jankovic-Karasoulos, T., Bianco-Miotto, T., Ryan, N. K., Thomas, M. R., Birrell, S. N., Butler, L. M., Tilley, W. D., & Hickey, T. E. (2014). Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo. Menopause, 21(1), 79-88. https://doi.org/10.1097/GME.0b013e3182936ef4