PROGESTERONE REGULATED EXPRESSION OF FLAVIN-CONTAINING MONOOXYGENASE-5 BY THE B-ISOFORM OF PROGESTERONE RECEPTORS - IMPLICATIONS FOR TAMOXIFEN CARCINOGENICITY

Progesterone is a key developmental, proliferative, and differentiativ e hormone in the breast and endometrium, and it can accelerate carcino genesis in the mammary gland epithelium. In the breast and uterus, pro gesterone acts through two coexpressed isoforms of progesterone recept ors, the B-and A-receptors. To study the function of each isoform in i solation, we previously constructed two breast cancer cell lines that stably and independently express either B-receptors (YB cells) or A-re ceptors (YA cells). In the present study, YA or YB cells were left unt reated, or were treated with the synthetic progestin R5020, and the me ssages present in each cell line under the two conditions were analyze d by differential display. Two message species are described that are regulated only by B-receptors. One of these is regulated in a ligand-i ndependent manner. A third set of messages, encoding flavin-containing monooxygenase 5 (FMO5), was induced by R5020 only in YB cells. A-rece ptors appear to be inhibitory. FMOs are involved in the metabolic acti vation of drugs and xenobiotic compounds, including the antiestrogen t amoxifen, to carcinogenic intermediates. It is possible, therefore, th at by upregulating the levels of FMO5, progesterone enhances the carci nogenicity of tamoxifen in target tissues that overexpress progesteron e B-receptors.