Progesterone-induced stimulation of mammary cell tumor initiation and growth in mice is due to the progesterone metabolite, 5alpha-dihydroprogesterone (5aP)

JOHN P. WIEBE, ROXANA SCHILLACI, PATRICIA V. ELIZALDE, MARTÍN A. RIVAS

Washington, DC, USA

Congreso; 91st Annual Meeting of the Endocrine Society of America; 2009

The Endocrine Society of America

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-GB; mso-fareast-language:EN-CA;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Previous studies have shown that  progesterone (P) is converted to 5a-dihydroprogesterone (5aP) in breast tissue and human breast cell lines by the action of 5a-reductase (5a-R) [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 in which the conversion of P to 5aP was blocked by a 5a-R inhibitor [5], provided proof-of-principle that the cancer promoting actions are indeed due to 5aP and not to P. The above were all in vitro studies and the objective of the studies reported here was to determine if 5aP has pro-cancer (i.e. tumor stimulating) activity in vivo.  METHODS. Balb/c mice were challenged with murine mammary (C4HD) tumor fragments, which have been shown to form tumors when treated with P [6]; the mice were treated (via sc suspensions) with various doses and combinations of P, 5aP and/or the 5a-R inhibitor, finasteride (FIN), and the effect on induction and growth of tumors was monitored. RESULTS. No tumors developed in vehicle-treated mice. A single treatment with P (20 mg) on day 0 resulted in development of tumors in 6/6 mice. 5aP treatment resulted in tiny nodules in 2/6 at 2 mg, 3/6 at 4 mg, 5/6 tumors (>100mm3; mean & SE = 200±40) at 10 mg, and 6/6 tumors (>160 mm3; mean & SE 456±81) at 30 days. Treatment with P (20 mg) plus 10, 20 or 40 mg FIN showed dose-dependent suppression of P-induced tumors due to FIN (Mean tumor size ±SE: P = 854±194; + 10 mg FIN = 356±129; + 20 mg FIN = 207±96; + 40 mg FIN = 144±60 mm3). In separate experiments, P (20 mg) resulted in 8/8 tumors, P + FIN (20 mg) resulted in 2/8 tumors, and P + FIN + 5aP (20 mg) resulted in full tumor development equal to P alone. CONCLUSIONS. The stimulation of C4HD tumor growth in Balb/c mice treated with P is due to the P metabolite 5aP, formed as a result of the 5a-R action on P. The P-sensitive C4HD tumor induction and growth is suppressed when P conversion to 5aP is blocked by 5a-R inhibition. This suppression is abrogated when FIN-treated mice are simultaneously treated with 5aP. These are the first in vivo studies indicating that 5aP acts as a cancer-promoting hormone that can stimulate mammary tumor induction and growth. (Supported by a grant to JPW from Susan G. Komen for the Cure)   References: [1] Wiebe JP et al., Cancer Res 2000; 60:936 [2] Wiebe JP & Lewis MJ, BMC Cancer 2003; 3:9 [3] Lewis MJ et al., BMC Cancer 2004; 4:27 [4] Wiebe JP, Endo Rel Cancer 2006; 13:717 [5] Wiebe et al., J Steroid Biochem Mol Biol 2006; 100:129 [6] Salatino M et al., Exp Cell Res 2001; 256:152.