Abstract
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 [3H]-E1 to [3H]-E1S or [3H]-E2S, while EOC cell lines mainly converted [3H]-E1 to [3H]-E2 with minimal formation of [3H]-E1S or [3H]-E2S. 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 E2 ‘activation’ from conjugated estrogen predominating in EOC. Inflammatory cytokines may further augment the local production of E2 by stimulating STS and suppressing EST. We conclude that local estrogen metabolism may be a target for EOC treatment.
Highlights
Estrogen is implicated in the progression of ovarian cancer, which is the most lethal of all gynecological malignancies
17BHSD5 mRNA expression was not affected by IL1a treatment (Fig. 7D). These results are suggestive that the key to estrogen generation in Epithelial ovarian cancer (EOC) cells may lie in their relative ability to convert conjugated estrogen substrates into free biologically active estrogens
We show for the first time that increased ratios of STS/estrogen sulfotransferase (EST) in EOC may facilitate local active estrogen synthesis in EOC and that inflammatory cytokines may trigger this synthesis in ovarian surface epithelium (OSE)
Summary
Estrogen is implicated in the progression of ovarian cancer, which is the most lethal of all gynecological malignancies. Ovarian cancer generally occurs in post-menopausal women when the ovary no longer actively secretes estrogen. This raises the question: if estrogen is involved, how is it produced?. Intracellular steroid activation through the STS pathway is involved in estrogen-dependent epithelial cancers, such as breast and endometrial carcinomas [10], and single nucleotide polymorphisms in SULT1E1 lead to increased risk of breast [11] and endometrial [12] cancers, together with reduced survival. We demonstrate that EOC and normal OSE cells do have distinct estrogen metabolizing signatures compatible with increased local generation of estrogen in ovarian cancer
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