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Progesterone Regulated Expression of Flavin-Containing Monooxygenase 5 by the B-Isoform of Progesterone Receptors: Implications for Tamoxifen Carcinogenicity

Department of Medicine, University of Colorado Health Sciences Center (M.M.M., R.A.J., J.K.R., D.F.G., W.M.W., K.B.H.), Denver, Colorado 80262; Departments of Obstetrics and Gynecology and Anatomy, McGill University (M.M.M.), Montreal, Quebec, Canada H3A 1A1; and Department of Medicine, University of Newcastle-Upon-Tyne (R.A.J.), Newcastle, NE2 4HH, United Kingdom

Address all correspondence and requests for reprints to: Kathryn B. Horwitz, Department of Medicine, Division of Endocrinology, Box B-151, University of Colorado Health Sciences Center, Denver, Colorado 80262.

Progesterone is a key developmental, proliferative, and differentiative hormone in the breast and endometrium, and it can accelerate carcinogenesis in the mammary gland epithelium. In the breast and uterus, progesterone acts through two coexpressed isoforms of progesterone receptors, the B- and A-receptors. To study the function of each isoform in isolation, we previously constructed two breast cancer cell lines that stably and independently express either B-receptors (YB cells) or A-receptors (YA cells). In the present study, YA or YB cells were left untreated, or were treated with the synthetic progestin R5020, and the messages present in each cell line under the two conditions were analyzed by differential display. Two message species are described that are regulated only by B-receptors. One of these is regulated in a ligand-independent manner. A third set of messages, encoding flavin-containing monooxygenase 5 (FMO5), was induced by R5020 only in YB cells. A-receptors appear to be inhibitory. FMOs are involved in the metabolic activation of drugs and xenobiotic compounds, including the antiestrogen tamoxifen, to carcinogenic intermediates. It is possible, therefore, that by upregulating the levels of FMO5, progesterone enhances the carcinogenicity of tamoxifen in target tissues that overexpress progesterone B-receptors.

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