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.
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.
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.
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.
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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
Received November 8, 2012; revised and accepted March 20, 2013.
A.M.O. and N.L.M. contributed equally to this work.
The contents of this published material are solely the responsibility of the authors and do not reflect the views of the National Health and Medical Research Council.
Funding/support: This work was supported by the National Health and Medical Research Council of Australia (1008349), Susan G. Komen for the Cure (BCTR0601118 and BCTR0504475), and the National Breast Cancer Foundation of Australia (NC-08-12 and NC-12-21). N.L.M., L.M.B., and T.B.-M. hold fellowships from Cancer Council South Australia. T.E.H. holds a postdoctoral fellowship award from the US Department of Defense Breast Cancer Research Program (W81XWH-11-1-0592).
Financial disclosure/conflicts of interest: W.D.T. has provided scientific expert opinion to Williams Love O’Leary and Powers PC (Portland, OR) regarding estrogen-progestin therapy and breast cancer risk and has consulted for Millennium Pharmaceuticals Inc. (Cambridge, MA) and Chavah Pty Ltd (Adelaide, Australia). The remaining authors declare no conflicts of interest.
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Address correspondence to: Wayne D. Tilley, PhD, Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, DX Number 650 801, Level 4, Hanson Institute Building, University of Adelaide, SA 5005, Australia. E-mail: email@example.com