FP07-1 Progesterone-induced stimulation of PR-positive murine mammary tumorigenesis is due to the progesterone metabolite, 5alpha-dihydroprogesterone (5aP)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP07-New Players in Hormonal Control of Breast & Prostate Cancer
Basic/Translational
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:00 AM
Room 206 (Moscone Center)

Poster Board SAT-295
John P Wiebe*1, Roxana Schillaci2, Patricia Virginia Elizalde2 and Martin Alfredo Rivas3
1Univ of Western Ontario, London, ON, Canada, 2Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina, 3Vall d'Hebron Institute of Oncology, Barcelona, Spain
Previous studies have shown that  progesterone (P) is converted to 5alpha-dihydroprogesterone (5aP) in breast tissue and human breast cell lines by the action of 5alpha-reductase (5a-red) [1-3], and that 5aP stimulates proliferation of human mammary cells in vitro regardless of their estrogen responsiveness, estrogen (ER)/progesterone (PR) receptor levels, and whether they are nontumorigenic or tumorigenic [1,4]. Studies with human breast cancer cells in which the conversion of P to 5aP was blocked by a 5a-red inhibitor [5] provided in vitro proof-of-principle that the cancer promoting actions are due to 5aP and not to P. The objective of the studies reported here was to determine in a P-sensitive in vivo mouse model if the presumptive P-induced mammary cell tumorigenesis is due to the 5aP metabolite. METHODS. BALBc mice were challenged with C4HD (ER+/PR+) murine mammary cells, which have been shown to form tumors when treated with the synthetic progestin MPA [6,7] or with P [8]. Cells and mice were treated with various doses and combinations of P, 5aP and/or the 5a-red inhibitor, finasteride (FIN), and the effects on cell proliferation (in vitro) and induction and growth of tumors (in vivo) were monitored. Hormone levels in serum and tumors were measured by specific RIA and ELISA tests. RESULTS. In vitro, C4HD cell proliferation was stimulated equally by treatment with P and 5aP; the increases with P were blocked by FIN and were reinstated with 5aP. In vivo, either 5aP or P induced tumorigenesis; the P-induced tumorigenesis was blocked by FIN and reinstated by concomitant treatment with 5aP. Hormone measurements showed significantly higher levels of 5aP in serum from mice with tumors (8.7 ±1.9 ng/ml) than without tumors (2.1±0.8 ng/ml) and significantly higher levels in tumors (32.7±6.0 ng/g) than in respective sera. CONCLUSIONS. The results indicate that the stimulation of C4HD tumor growth in BALBc mice treated with P is due to the P metabolite 5aP, formed at elevated levels in mammary tumors as a result of the 5a-red action on P. These are the first in vivo studies indicating that the P metabolite 5aP, rather than P itself, is the cancer-promoting hormone that stimulates tumor induction and growth in ER+/PR+ breast cells exposed to progesterone.

[1] Wiebe JP, et al., Cancer Res 2000; 60:936-943. [2] Wiebe JP & Lewis MJ, BMC Cancer 2003; 3:9. [3] Lewis MJ, et al., BMC Cancer 2004; 4:27. [4] Wiebe JP, et al., J Steroid Biochem Mol Biol 2010; 118:125-132. [5] Wiebe JP, et al., J Steroid Biochem Mol Biol 2006; 100:129-140. [6] Elizalde PV, et al., Breast Cancer Res Treat 1990; 16:29-39. [7] Beguelin W, et al. Mol Cell Biol 2010; 30:5456-72. [8] Kordon EC et al., Breast Cancer Res Treat 1993; 28:29-39.

Nothing to Disclose: JPW, RS, PVE, MAR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Canadian Institutes of Health Research; Susan G. Komen for the Cure
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