Regulation of sex steroid formation by interleukin-4 and interleukin-6 in breast cancer cells.
Sex steroids play a predominant role in the development and differentiation of normal mammary gland as well as in the regulation of hormone-sensitive breast cancer growth. There is evidence suggesting that local intracrine formation of sex steroids from inactive precursors secreted by the adrenals namely, dehydroepiandrosterone (DHEA) and 4-androstenedione (4-dione) play an important role in the regulation of growth and function of peripheral target tissues, including the breast. Moreover, human breast carcinomas are often infiltrated by stromal/immune cells secreting a wide spectra of cytokines. These might in turn regulate the activity of both immune and neoplastic cells. The present study was designed to examine the action of cytokines on 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) activities in human breast cancer cells. The various types of human 17beta-HSD (five types) and 3beta-HSD (two types), because of their tissue- and cell-specific expression and substrate specificity, provide each cell with necessary mechanisms to control the level of intracellular active androgens and estrogens. We first investigated the effect of exposure to IL-4 and IL-6 on reductive and oxidative 17beta-HSD activities in both intact ZR-75-1 and T-47D human breast cancer cells. In ZR-75-1 cells, a 6 d exposure to IL-4 and IL-6 decreased E2-induced cell proliferation, the half maximal inhibitory effect being exerted at 88 and 26 pM, respectively. In parallel, incubation with IL-4 and IL-6 increased oxidative 17beta-HSD activity by 4.4- and 1.9-fold, respectively, this potent activity being observed at EC50 values of 22.8 and 11.3 pM, respectively. Simultaneously, reductive 17beta-HSD activity leading to E2 formation was decreased by 70 and 40% by IL-4 and IL-6, respectively. Moreover, IL-4 and IL-6 exerted the same regulatory effects on 17beta-HSD activities when testosterone and 4-dione were used as substrates, thus strongly suggesting the expression of the type 2 17beta-HSD ZR-75-1 cells. In contrast, in T-47D cells, IL-4 increased the formation of E2, whereas IL-6 exerts no effect on this parameter. However, we found that T-47D cells failed to convert testosterone efficiently into 4-DIONE, thus suggesting that there is little or no expression of type 2 17beta-HSD in this cell line. The present findings demonstrate that the potent regulatory effects of IL-4 and IL-6 on 17beta-HSD activities depend on the cell-specific gene expression of various types of 17beta-HSD enzymes. We have also studied the effect of cytokines on the regulation of the 3beta-HSD expression in both ZR-75-1 and T-47D human breast cancer cells. Under basal culture conditions, there is no 3beta-HSD activity detectable in these cells. However, exposure to IL-4 caused a rapid and potent induction of 3beta-HSD activity, whereas IL-6 failed to induce 3beta-HSD expression. Our data thus demonstrate that cytokines may play a crucial role in sex steroid biosynthesis from inactive adrenal precursors in human breast cancer cells.
Medical Research Council Group in Molecular Endocrinology, CHUL Research Center and Laval University, Québec, Canada.
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Turgeon
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Gingras
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Carrière
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Blais
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D015067:17-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis; D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002474:Cell-Free System; D004347:Drug Interactions; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013256:Steroids / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D012739:Gonadal Steroid Hormones; D015850:Interleukin-6; D013256:Steroids; D015847:Interleukin-4; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases