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17ß-Estradiol Induces Down-Regulation of Cap43/NDRG1/Drg-1, a Putative Differentiation-Related and Metastasis Suppressor Gene, in Human Breast Cancer Cells

Authors' Affiliations: ¹ Center for Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science and Departments of ² Surgery and ³ Pathology, Kurume University, Kurume, Japan and ⁴ Station-II for Collaborative Research and ⁵ Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Requests for reprints: Teruhiko Fujii, Center for Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science, Kurume University, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. Phone: 81-942-31-7748; Fax: 81-942-31-7749; E-mail: tfujii{at}med.kurume-u.ac.jp.

Purpose: Cap43 is known as a nickel- and calcium-inducible gene. In the present study, we examined whether 17ß-estradiol (E₂) could affect the expression of Cap43 in breast cancer.

Experimental Design: Real-time PCR, immunoblotting, and immunocytochemistry were used to examine the expression of Cap43 and estrogen receptor- (ER-) in breast cancer cell lines. MDA-MB-231 and SK-BR-3 cell lines were transfected with ER- cDNA to establish cells overexpressing ER-. Immunohistochemistry was used to evaluate the expression of the Cap43 protein in breast cancer patients (n = 96), and the relationship between Cap43 expression and clinicopathologic findings was examined.

Results: Of the eight cell lines, four expressed higher levels of Cap43 with very low levels of ER-, whereas the other four expressed lower levels of Cap43 with high ER- levels. Treatment with E₂ decreased the expression of Cap43 dose-dependently in ER--positive cell lines but not in ER--negative lines. Administration of antiestrogens, tamoxifen and ICI 182780, abrogated the E₂-induced down-regulation of Cap43. Overexpression of ER- in both ER--negative cell lines, SK-BR-3 and MDA-MB-231, resulted in down-regulation of Cap43. Immunostaining studies showed a significant correlation between Cap43 expression and the histologic grade of tumors (P = 0.0387). Furthermore, Cap43 expression was inversely correlated with the expression of ER- (P = 0.0374).

Conclusions: E₂-induced down-regulation of Cap43 seems to be mediated through ER--dependent pathways in breast cancer cells both in culture and in patients. Cap43 has potential as a molecular marker to determine the therapeutic efficacy of antiestrogenic anticancer agents in breast cancer.

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