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

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), 17β-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 [(3)H]-E(1) to [(3)H]-E(1)S or [(3)H]-E(2)S, while EOC cell lines mainly converted [(3)H]-E(1) to [(3)H]-E(2) with minimal formation of [(3)H]-E(1)S or [(3)H]-E(2)S. IL1α 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.