Circulating Estrogens in Endometrial Cancer Cases and Their Relationship with Tissular Expression of Key Estrogen Biosynthesis and Metabolic Pathways

Abstract

AbstractBackground: Endometrial cancer is the most common gynecological malignancy. Estrogen exposure is strongly associated with endometrial cancer. Whereas this cancer occurs predominantly in postmenopausal women lacking estrogen production by ovaries, the conversion of adrenal androgen-estrogen precursors to estradiol (E2), estrone (E1), and its sulfate (E1-S) has been well documented in peripheral tissues.Experimental Design: We initially explored whether circulating levels of estrogens, measured by validated mass spectrometry assays, differ in women with endometrial cancer (n = 126) compared with healthy women (n = 110). We then evaluated by quantitative real-time PCR from purified RNA whether the expression profile of 19 estrogen-related synthesis and metabolic genes is modified in peritumoral normal endometrium (n = 36) compared with tumoral (n = 49) tissues.Results: In endometrial cancer cases, circulating levels of E1, E2, and E1-S were significantly higher compared with unaffected controls. In agreement with plasma levels, findings support an enhanced biosynthesis of E2 in tumors. The expression of E2 biosynthesis pathways [E1-S (sulfatase) → E1 (17β-hydroxysteroid dehydrogenase) → E2] was shown to predominate in peritumoral normal endometrium and was significantly increased in tumors. In addition, the inactivation pathways mediated by several uridine diphosphate-glucuronosyltransferases were also enhanced in endometrial tumors compared with peritumoral normal endometrium.Conclusion: We concluded that the higher levels of circulating estrogens in women with endometrial cancer are likely associated with an imbalance of multiple biotransformation pathways in endometrial tumor tissues.