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Estrogen Inhibits Cell Proliferation through In situ Production in Human Thymoma

Authors' Affiliations: ¹ Department of Pathology, Tohoku University School of Medicine; ² Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; ³ Department of Thoracic Surgery, Iwate General Hospital, Morioka, Japan; ⁴ Thoracic Cardiovascular Surgery, Graduate School, Tokyo Medical and Dental University; and ⁵ Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan

Requests for reprints: Hironori Ishibashi, Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi Aoba-ku, Sendai, Miyagi Prefecture 980-0875, Japan. Phone: 81-22-717-8521; Fax: 81-22-717-8526; E-mail: hishiba{at}kf6.so-net.ne.jp.

Purpose: We showed previously estrogen receptor (ER) as an independent prognostic marker in human thymoma. Estrogen sulfotransferase (EST), steroid sulfatase (STS), 17ß-hydroxysteroid dehydrogenase (17ß-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 ER in TEC, which synthesized estrone and E₂. Intratumoral E₂ concentrations were inversely correlated with EST, positively correlated with STS or 17ß-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 17ß-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 ER, 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.

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