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Overexpression of progesterone receptor membrane component 1: possible mechanism for increased breast cancer risk with norethisterone in hormone therapy

Neubauer, Hans PhD1; Ruan, Xiangyan MD2; Schneck, Helen1; Seeger, Harald PhD1; Cahill, Michael A. PhD3; Liang, Yayun PhD4; Mafuvadze, Benfor PhD4; Hyder, Salman M. PhD4; Fehm, Tanja MD1; Mueck, Alfred O. MD, PharmD, PhD1

Menopause: The Journal of The North American Menopause Society: May 2013 - Volume 20 - Issue 5 - p 504–510
doi: 10.1097/gme.0b013e3182755c97
Original Articles

Objective Clinical trials have demonstrated an increased risk of breast cancer during estrogen/norethisterone (NET) therapy. With this in mind, the effects of estrogen/NET combination on the proliferation of breast cancer cells overexpressing the progesterone receptor membrane component 1 (PGRMC1) were examined. The same combination was used for the first time in a mouse xenograft model to determine its effects on tumor development.

Methods MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells) or empty vector control (pcDNA-3HA). NET, medroxyprogesterone acetate (MPA), and progesterone were tested alone and sequentially and continuously combined with estradiol (E2). Six-week-old nude mice were inoculated with E2 pellets 24 hours before the injection of tumor cells into both flanks (n = 5-6 mice per group). After 8 days, animals were inoculated with a NET pellet or with placebo pellets, and tumor volumes were recorded twice a week.

Results NET alone significantly increased the proliferation of WT-12 cells, MPA was effective only at the two highest concentrations, and progesterone had no effect. The twofold to threefold E2-induced increase (10−10 M) was not significantly influenced by the addition of the various progestogens. In contrast, 10−12 M E2 had no effect; however, addition of MPA and NET triggered a significant proliferative response. In vivo, a sequential combination of NET and E2 also significantly increased the tumor growth of WT-12 cells; empty vector cells did not respond to NET.

Conclusions We have demonstrated for the first time that an E2/NET combination increases the proliferation of PGRMC1-overexpressing breast cancer cells, both in vivo and in vitro. Our results suggest that undetected tumor cells overexpressing PGRMC1 may be more likely to develop into frank tumor cells in women undergoing E2/NET hormone therapy.

From the 1University Women’s Hospital, Tuebingen, Germany; 2Department of Gynecological Endocrinology, Beijing OB/GYN Hospital, Capital Medical University, Beijing, China; 3School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia; and 4Dalton Cardiovascular Research Center, Department of Biomedical Sciences, University of Missouri, Columbia, MO.

Received July 9, 2012; revised and accepted September 20, 2012.

Funding/support: This work was supported by grants to X.R. for scholarships in clinical pharmacology at the University of Tuebingen through the Beijing Municipality Health Technology High-Level Talent (no. 2009-3-52) and the National Natural Science Foundation (no. 81172518).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Alfred O. Mueck, MD, PharmD, PhD, Center of Women’s Health BW, Department of Endocrinology and Menopause, University Women’s Hospital, Calwer Strasse 7, Tuebingen D-72076, Germany. E-mail:

© 2013 by The North American Menopause Society.