Possible mechanism for the observed increased breast cancer risk using norethisterone in hormone therapy
Xiangyan Ruan1, Hans Neubauer2, Harald Seeger2, Tanja Fehm2, Alfred O Mueck2
1 Dept. of Gynecol. Endocrinology, Beijing Ob/Gyn Hospital; Capital Medical University, Beijing, China
2 University Women’s Hospital, Tuebingen, Germany
Objectives: Some clinical trials showed an increased risk especially during HRT containing estrogen/norethisterone preparations. In the present work the effect of a sequential HRT estradiol/norethisterone combination was investigated on the proliferation of MCF-7 breast cancer cells overexpressing the progesterone receptor membrane component 1 (PGRMC1). We already have demonstrated that this component is important in the tumorgenesis of breast cancer and progestogens added to estrogen may have different effects on its upregulation (Menopause 2011; 18: 845-850; Editorial 18:833-834). For the first time this combination was tested additionally in a mouse transplantation model.
Methods: MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells). In cell experiments estradiol (E2) in the concentrations 10-12 und 10-10 M was sequentially combined with norethisterone (NET, 10-7 M). Proliferation was measured by MTT test. Six weeks old nude mice were inoculated with E2 pellets (0.72mg/60 day release) 24 hours before tumor cell injections into both flank. WT-12 cells or MCF-7 cells transfected with an empty vector control were injected into each flank of an individual mouse, respectively. After eight days animals were inoculated with a NET pellet (10 mg/60 day release) or control pellets, and tumor volumes were recorded twice a week.
Results: The E2/NET combination increased the proliferation of WT-12 cells by 2-3 fold as compared to wild-type MCF-7 cells. NET also increased tumor growth of WT-12 cells in vivo. Empty vector cells do not react to NET.
Conclusion: For the first time we could show that an estradiol/norethisterone combination increases the proliferation of breast cancer cells in a cell experiment as well as in an animal experiment at least in breast cancer cells overexpressing PGRMC1. Thus further research should evaluate if women, especially those overexpressing PGRMC1, have an increased breast cancer risk during estradiol/norethisterone therapy.
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