title: Local estrogen metabolism in epithelial ovarian cancer suggests novel targets for therapy.
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 [(3)H]-E1 to [(3)H]-E1S or [(3)H]-E2S, while EOC cell lines mainly converted [(3)H]-E1 to [(3)H]-E2 with minimal formation of [(3)H]-E1S or [(3)H]-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.
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom.
authors.forename: Xia
authors.initials: X
authors.lastname: Ren
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Hillier
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom.
authors.forename: K Scott
authors.initials: KS
authors.lastname: Fegan
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom.
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom.
authors.forename: J Ian
authors.initials: JI
authors.lastname: Mason
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom.
authors.forename: Sana
authors.initials: S
authors.lastname: Sarvi
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, United Kingdom. Electronic address: c.harlow@ed.ac.uk.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Harlow
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001711:Biotransformation; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004960:Estradiol Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000494:pharmacology; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043266:Steryl-Sulfatase / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014316:Tritium
chemical_list: D004967:Estrogens; C508584:IL1A protein, human; D053582:Interleukin-1alpha; D012333:RNA, Messenger; D014316:Tritium; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human; D015238:Sulfotransferases; C020122:estrone sulfotransferase; D043266:Steryl-Sulfatase
keywords: Epithelial ovarian cancer; Estrogen; Estrogen sulfotransferase; Ovarian surface epithelium; Steroid sulfatase
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