期刊
INTERNATIONAL JOURNAL OF CANCER
卷 122, 期 9, 页码 1931-1940出版社
WILEY-LISS
DOI: 10.1002/ijc.23350
关键词
breast cancer; hormone-dependent; 17 beta-hydroxysteroid dehydrogenase Type 1 and Type 12 (17 beta-HSD1 & 12); STX1040
类别
资金
- NCI NIH HHS [R50 CA211447] Funding Source: Medline
Oestradiol (E2) stimulates the growth of hormone-dependent breast cancer. 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) catalyse the pre-receptor activation/inactivation of hormones and other substrates. 17 beta-HSD1 converts oestrone (E1) to active E2, but it has recently been suggested that another 17 beta-HSD, 17 beta-HSD12, may be the major enzyme that catalyses this reaction in women. Here we demonstrate that it is 17 beta-HSD1 which is important for E2 production and report the inhibition of El-stimulated breast tumor growth by STX1040, a non-oestrogenic selective inhibitor of 17 beta-HSD1, using a novel murine model. 17 beta-HSD1 and 17 beta-HSD12 mRNA and protein expression, and E2 production, were assayed in wild type breast cancer cell lines and in cells after siRNA and cDNA transfection. Although 17 beta-HSD12 was highly expressed in breast cancer cell lines, only 17 beta-HSD1 efficiently catalysed E2 formation. The effect of STX1040 on the proliferation of E1-stimulated T47D breast cancer cells was determined in vitro and in vivo. Cells inoculated into ovariectomised nude mice were stimulated using 0.05 or 0.1 mu g E1 (s.c.) daily, and on day 35 the mice were dosed additionally with 20 mg/kg STX1040 s.c. daily for 28 days. STX1040 inhibited E1-stimulated proliferation of T47D cells in vitro and significantly decreased tumor volumes and plasma E2 levels in vivo. In conclusion, a model was developed to study the inhibition of the major oestrogenic 17 beta-HSD, 17 beta-HSD1, in breast cancer. Both E2 production and tumor growth were inhibited by STX1040, suggesting that 17 beta-HSD1 inhibitors such as STX1040 may provide a novel treatment for hormone-dependent breast cancer. (C) 2008 Wiley-Liss, Inc.
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