Background: Approximately 30% of breast tumors do not express the estrogen receptor (ER) a, which is necessary\r\nfor endocrine therapy approaches. Studies are ongoing in order to restore ERa expression in ERa-negative breast\r\ncancer. The aim of the present study was to determine if calcitriol induces ERa expression in ER-negative breast\r\ncancer cells, thus restoring antiestrogen responses.\r\nMethods: Cultured cells derived from ERa-negative breast tumors and an ERa-negative breast cancer cell line\r\n(SUM-229PE) were treated with calcitriol and ERa expression was assessed by real time PCR and western blots. The\r\nERa functionality was evaluated by prolactin gene expression analysis. In addition, the effects of antiestrogens were\r\nassessed by growth assay using the XTT method. Gene expression of cyclin D1 (CCND1), and Ether-� -go-go 1 (EAG1)\r\nwas also evaluated in cells treated with calcitriol alone or in combination with estradiol or ICI-182,780. Statistical\r\nanalyses were determined by one-way ANOVA.\r\nResults: Calcitriol was able to induce the expression of a functional ERa in ER-negative breast cancer cells. This\r\neffect was mediated through the vitamin D receptor (VDR), since it was abrogated by a VDR antagonist. Interestingly,\r\nthe calcitriol-induced ERa restored the response to antiestrogens by inhibiting cell proliferation. In addition,\r\ncalcitriol-treated cells in the presence of ICI-182,780 resulted in a significant reduction of two important cell\r\nproliferation regulators CCND1 and EAG1.\r\nConclusions: Calcitriol induced the expression of ERa and restored the response to antiestrogens in ERa-negative\r\nbreast cancer cells. The combined treatment with calcitriol and antiestrogens could represent a new therapeutic\r\nstrategy in ERa-negative breast cancer patients.
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