Progesterone plays an essential role in breast development and cancer formation. The local metabolism of progesterone may limit its interactions with the progesterone receptor (PR) and thereby act as a prereceptor regulator. Selective loss of AKR1C1, which encodes a 20␣-hydroxysteroid dehydrogenase [20␣-HSD (EC 1.1.1.149)], and AKR1C2, which encodes a 3␣-hydroxysteroid dehydrogenase [3␣-HSD (EC 1.1.1.52)], was found in 24 paired breast cancer samples as compared with paired normal tissues from the same individuals. In contrast, AKR1C3, which shares 84% sequence identity, and 5␣-reductase type I (SRD5A1) were minimally affected. Breast cancer cell lines T-47D and MCF-7 also expressed reduced AKR1C1, whereas the breast epithelial cell line MCF-10A expressed AKR1C1 at levels comparable with those of normal breast tissues. Immunohistochemical staining confirmed loss of AKR1C1 expression in breast tumors. AKR1C3 and AKR1C1 were localized on the same myoepithelial and luminal epithelial cell layers. Suppression of ARK1C1 and AKR1C2 by selective small interfering RNAs inhibited production of 20␣-dihydroprogesterone and was associated with increased progesterone in MCF-10A cells. Suppression of AKR1C1 alone or with AKR1C2 in T-47D cells led to decreased growth in the presence of progesterone. Overexpression of AKR1C1 and, to a lesser extent, AKR1C2 (but not AKR1C3) decreased progesterone-dependent PR activation of a mouse mammary tumor virus promoter in both prostate (PC-3) and breast (T-47D) cancer cell lines. We speculate that loss of AKR1C1 and AKR1C2 in breast cancer results in decreased progesterone catabolism, which, in combination with increased PR expression, may augment progesterone signaling by its nuclear receptors.

Ovarian cancer (OC) is one of the leading causes of death in patients with gynecologic malignancies. The vast majority of ovarian cancers have a cell origin of ovarian surface epithelium (OSE), which is derived from Mullerian epithelium covering embryonic gonads. Since the incidence of OC sharply increases after menopause, critical roles of gonadotropins and their receptors in ovarian carcinogenesis are speculated by investigators. 1 Follicle stimulating hormone (FSH), through interaction with its specific receptor, FSHR, plays an essential role in mammalian reproduction and ovarian folliculogenesis. 2 Binding of FSH to FSHR results in adenylyl cyclase activation leading to cAMP synthesis, associated with intracellular rise of Ca 2ϩ , activation of protein kinase A (PKA) and other downstream signal transduction pathways. [2][3][4][5][6] It has been reported that FSH treatment stimulates cell proliferation on normal human OSE cells, immortalized OSE cells and OC cell lines. 7,8 However, little has been known on the effects of FSH in the process of tumorigenesis and growth stimulation on human OSE at molecular levels.In this study, we first determined FSHR expression levels quantitatively in human ovarian normal and neoplastic tissues. Then the effects of FSH treatment on cell proliferation were examined using human OSE cell lines as well as Chinese hamster ovary (CHO) cell lines permanently transfected with human FSHR. Finally, gene expression profiles for FSH treatment were analyzed by cDNA MicroArray using a selected human OSE cell line that has best growth response to FSH treatment from cell proliferation assays. MATERIAL AND METHODS

No abstract