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¹ Reproductive Health Research, Training and Communication Unit, School of Medicine, Universidad Nacional Autónoma de México, Hospital General de México and Instituto Nacional de Perinatología, México City, México
² Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición S. Zubirán, México City, México
³ Department of Reproductive Biology, Universidad Autónoma Metropolitana Iztapalapa, Av. San Rafael Atlixco 186, Colonia Vicentina, Delegación Iztapalapa, México City, México

(Requests for offprints should be addressed to A E Lemus; Email: anaelenalemus{at}aol.com)

Breast cancer is a sex steroid hormone-dependent malignant neoplasia. The role of oestradiol in this malignancy has been well documented; however, the involvement of androgens has remained controversial. To determine the role of non-phenolic androgen metabolites in human breast cancer, we studied the metabolism of [¹⁴C] testosterone and [¹⁴C] androstenedione in oestrogen-dependent MCF-7 cells and non-oestrogen-dependent MDA-MB 231 cells, at different substrate concentrations (1–10 µM) and time periods (30 min–48 h). Cultured non-oestrogen-dependent HeLa and yeast cells served as controls. Metabolites were identified and quantified by reverse isotope dilution. A distinctive pattern of androgen metabolism was identified in MCF-7 cells, being the 5-androstane-3,17ß-diol (3,5-diol) and its 3ß epimer (3ß,5-diol), the major conversion products of testosterone (48.3%), with 5-dihydrotestosterone as intermediary. The formation of 3,5-diol and 3ß,5-diol (diols) was substrate concentration- and time-dependent, and abolished by finasteride. In contrast, very little of any diol formation was observed in MDA-MB 231, HeLa and yeast cell incubations. Additional enzyme gene expression studies revealed an overexpression of 5-steroid reductase type-1 in MCF-7 cells, as compared with MDA-MB 231 cells. The oestrogen-like activities of diols were assessed in HeLa cells co-transfected with expression vectors for or ß subtypes of the human oestrogen receptor (hER) genes and for an oestrogen-responsive reporter gene. The results show that 3ß, 5-diol and to a lesser extent 3,5-diol bind with high relative affinity to hER and hERß.

Both diols induced hER-mediated reporter gene transactivation in a dose–response manner, similar to that induced by oestradiol, though with lower potency, an effect that was abolished by ICI-182 780. Furthermore, 3ß,5-diol and to lesser extent 3,5-diol induced MCF-7 cell proliferation. The overall results demonstrated that MCF-7 cells exhibit enhanced expression and activity of androgen-metabolising enzymes, leading to rapid and large diol formation, and provide evidence that these androgen metabolites exert a potent oestrogen-agonistic effect, at genomic level, in oestrogen-dependent breast cancer cells. The data suggest that diols may act as in situ intracrine factors in breast cancer and that its formation can be pharmacologically inhibited.

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				J. Enriquez, A. E. Lemus, J. Chimal-Monroy, H. Arzate, G. A Garcia, B. Herrero, F. Larrea, and G. Perez-Palacios The effects of synthetic 19-norprogestins on osteoblastic cell function are mediated by their non-phenolic reduced metabolites J. Endocrinol., June 1, 2007; 193(3): 493 - 504. [Abstract] [Full Text] [PDF]