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

PURPOSE: Cap43 is known as a nickel- and calcium-inducible gene. In the present study, we examined whether 17{beta}-estradiol (E sub(2)) 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- alpha (ER- alpha ) in breast cancer cell lines. MDA-MB-231 and SK-BR-3 cell lines were transfected with ER- alpha cDNA to establish cells overexpressing ER- alpha . 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- alpha , whereas the other four expressed lower levels of Cap43 with high ER- alpha levels. Treatment with E sub(2) decreased the expression of Cap43 dose-dependently in ER- alpha -positive cell lines but not in ER- alpha -negative lines. Administration of antiestrogens, tamoxifen and ICI 182780, abrogated the E sub(2)-induced down-regulation of Cap43. Overexpression of ER- alpha in both ER- alpha -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- alpha (P = 0.0374). CONCLUSIONS: E sub(2)-induced down-regulation of Cap43 seems to be mediated through ER- alpha -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.