Overexpression of progesterone receptor membrane component 1: possible mechanism for increased breast cancer risk with norethisterone in hormone therapy
ABSTRACT 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.
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.
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 M) was not significantly influenced by the addition of the various progestogens. In contrast, 10 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.
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.
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ABSTRACT: Hormone therapy may increase the risk of breast cancer. Thus, especially the addition of synthetic progestins may play a decisive role according to the results of clinical studies. Overexpression of a special receptor, i.e. the progesterone receptor membrane component-1 (PGRMC1), may offer a potential new pathway to explain the observed increase in breast cancer risk in the combined arm of the Women's Health Initiative. PGRMC1 is expressed in breast cancer tissue and may be important in tumorigenesis. The expression of PGRMC1 in breast cancer tissue is significantly different from that in normal mammary glands. Certain synthetic progestins can increase the proliferation of PGRMC1-overexpressing breast cancer cells and may thus be involved in tumorigenesis, while progesterone and certain synthetic progestins such as nomegestrol or chlormadinone acetate react neutrally. Our investigations point towards an important role of estrogen receptor-α in the signaling cascade, resulting in the proliferative effect induced by progestins. Thus, activation of PGRMC1 may explain the increased breast cancer risk observed during treatment with certain progestins. Very recently, PGRMC1 was investigated in serum samples of lung cancer patients and matched healthy patients; significantly higher concentrations were shown in the cancer patients. Therefore, PGRMC1 might be a predictor for other cancers as well but, according to clinical trials, its importance for a possible screening tool, particularly for breast cancer risk during hormone therapy, seems of interest.Climacteric 06/2013; DOI:10.3109/13697137.2013.800038 · 2.24 Impact Factor