Estrogen inhibits cell proliferation through in situ production in human thymoma

Purpose: We showed previously estrogen receptor (ER) α as an independent prognostic marker in human thymoma. Estrogen sulfotransferase (EST), steroid sulfatase (STS), 17β-hydroxysteroid dehydrogenase (17β-HSD), and aromatase are considered to play important roles in hormone metabolism of estrogen-dependent tumors. Experimental Design: We examined estrogen production using primary cultures of human thymoma epithelial cells (TEC), intratumoral estradiol (E₂) concentrations, and status of these enzymes above using immunohistochemistry or semiquantitative reverse transcription-PCR. We then correlated these findings with clinicopathologic variables and/or clinical outcome in 132 patients. Results: E₂ inhibited cell proliferation via ERα in TEC, which synthesized estrone and E₂. Intratumoral E₂ concentrations were inversely correlated with EST, positively correlated with STS or 17β-HSD type 1, and significantly higher in lower-grade or early-stage thymoma. EST status was positively correlated with tumor size, clinical stage, histologic differentiation, and Ki-67 labeling index and significantly associated with adverse clinical outcome and turned out to be a potent independent prognostic factor. STS and/or 17β-HSD type 1 status was inversely correlated with Ki-67 labeling index and associated with lower histologic grade or early clinical stages. Conclusions: E₂ inhibits proliferation of TEC through ERα, which suggests that E₂ may be effective in treatment of thymoma, especially inoperable tumor, possibly through suppressing its cell proliferation activity. EST status is a potent prognostic factor in thymoma through inactivating estrogens. In situ estrogen synthesis through intracrine mechanism therefore may play important roles in tumorigenesis and/or development of thymoma through regulation of cell proliferation in an intracrine manner.