Local estrogen metabolism in epithelial ovarian cancer suggests novel targets for therapy

摘要

Epithelial ovarian cancer (EOC) accounts for about 90% of malignant ovarian tumors, and estrogen is often implicated in disease progression. We therefore compared the potential for gating of estrogen action via pre-receptor metabolism in normal human ovarian surface epithelium (OSE), EOC and selected EOC cell lines (SKOV3 and PEO1). Steroid sulphatase (STS), estrogen sulfotransferase (EST), 17 beta-hydroxysteroid dehydrogenases 2 (17BHSD2) and 5 (17BHSD5) mRNAs, proteins and enzymatic activities were all detectable in primary cell cultures of OSE and EOC, whereas aromatase and 17BHSD1 expression was negligible. qRT-PCR assay on total mRNA revealed significantly higher EST mRNA expression in OSE compared to EOC (P<0.05). Radioenzymatic measurements confirmed reduced sulfoconjugation (neutralization) of free estrogen in EOC relative to OSE. OSE cells were more effective at converting free [H-3]-E-1 to [H-3]-E1S or [H-3]-E2S, while EOC cell lines mainly converted [H-3]-E-1 to [H-3]-E-2 with minimal formation of [H-3]-E1S or [H-3]-E2S. IL1 alpha treatment suppressed EST (P < 0.01) and 17BHSD2 (P < 0.001) mRNA levels in OSE and stimulated STS mRNA levels (P < 0.001) in cancer (SKOV3) cells. These results show that estrogen is differentially metabolized in OSE and EOC cells, with E-2 'activation' from conjugated estrogen predominating in EOC. Inflammatory cytokines may further augment the local production of E-2 by stimulating STS and suppressing EST. We conclude that local estrogen metabolism may be a target for EOC treatment. (C) 2015 The Authors. Published by Elsevier Ltd.