Progesterone metabolites regulate induction, growth and suppression of ER/PR-negative human breast cell tumors

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-305
John P Wiebe*
Univ of Western Ontario, London, ON, Canada
Many breast cancer cases (30%-60%) lack estrogen receptors (ER) and/or progesterone receptors (PR).  These hormone receptor negative (HR-neg) breast cancers are not explained by E or P actions, do not respond to E- or P-based therapies and are generally more aggressive than HR-positive breast cancers. Previous in vitro studies had shown that the progesterone metabolites (PMs), 5alpha-dihydroprogesterone (5aP) and 3alpha-dihydroprogesterone (3aHP), respectively, exhibit pro- and anti-proliferative effects on various human breast cell lines [1,2], via actions on specific membrane based receptors [3,4] and cell signaling pathways [5,6]. Here the first in vivo studies (using human-mouse xenografts) were conducted to determine if PMs control HR-neg breast tumors and tumorigenesis. Methods: Human breast cells (MDA-MB-231; M231; ER/PR-negative) were implanted into mammary fat pads of SCID mice and the effects of vehicle (control), 5aP and 3aHP on tumor initiation, growth, suppression/regression and histopathology were assessed in 5 separate experiments. Specific RIAs and GC-MS were used to measure 5aP, 3aHP and P in mouse serum and tumors. Results: Onset and growth of M231 tumors were significantly stimulated by 5aP and inhibited by 3aHP. When both hormones were applied simultaneously, the stimulatory effects of 5aP were abrogated by the inhibitory effects of 3aHP and vice versa. Treatment with 3aHP subsequent to 5aP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. In tumors 5aP levels were ~10-fold higher than 3aHP levels (regardless of treatment), and 5aP:3aHP ratios were ~5-fold higher than in serum, indicating significant increases in 5aP in the tumor microenvironment. Conclusions: The studies show that HR-neg human breast cells and tumors are sensitive to, and controlled by, the PMs 5aP and 3aHP: tumorigenesis is significantly enhanced by 5aP and suppressed by 3aHP, the outcome depending upon the relative concentration of each. The findings provide new understanding of hormonal controls of HR-neg breast cancers and suggest new diagnostic biomarkers and new approaches to prevention and treatment of breast cancers, based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.

[1] Wiebe JP, et al. Cancer Res 2000; 60:936-943. [2] Wiebe JP, et al. J Steroid Biochem Mol Biol 2010; 118:125-132. [3] Weiler PJ & Wiebe JP, Biochem Biophys Res Commun 2000; 272:731-737. [4] Pawlak KJ, et al. J Steroid Biochem Mol Biol 2005; 97:278-288. [5] Wiebe JP & Muzia D. Endocrine 2001; 16:7-14. [6] Wiebe JP. Endocr Rel Cancer 2006;13:717-738.

Nothing to Disclose: JPW

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