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1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the active metabolite of vitamin D3, is a potent inhibitor of breast cancer cell growth both in vivo and in vitro. We have previously demonstrated that 1,25-(OH)2D3 induces morphology (pyknotic nuclei, chromatin and cytoplasmic condensation, and nuclear matrix protein reorganization) consistent with the activation of apoptosis in MCF-7 cells. These morphological changes in 1,25-(OH)2D3-treated cells are associated with up-regulation of TRPM-2/clusterin and cathepsin B (genes associated with mammary gland apoptosis) and down-regulation of bcl-2, an antiapoptotic gene. Thus, the inhibitory effects of 1,25-(OH)2D3 on MCF-7 cell growth involve activation of apoptosis. To investigate the mechanisms by which vitamin D3 activates apoptosis, we have selected a vitamin D3-resistant variant (MCF-7D3Res cells) by continuous culture of MCF-7 cells in 100 nM 1,25-(OH)2D3. The MCF-7D3Res cells represent a stably selected phenotype that grows equally well with or without 100 nM 1,25-(OH)2D3. In contrast to the MCF-7 cells from which they were derived (MCF-7WT cells), MCF-7D3Res cells do not exhibit apoptotic morphology, DNA fragmentation, or up-regulation of apoptosis-related proteins after treatment with 1,25-(OH)2D3. MCF-7D3Res cells exhibit cross-resistance to several vitamin D3 analogs that are potent growth regulators of MCF-7WT cells. MCF-7WT and MCF-7D3Res cells exhibit comparable sensitivity to induction of apoptosis and up-regulation of clusterin in response to the antiestrogen 4-hydroxytamoxifen. MCF-7D3Res cells express comparable levels of the vitamin D receptor (VDR), as assessed by Western blotting or ligand binding, as MCF-7WT cells. In both sensitive and resistant cell lines, 1,25-(OH)2D3 up-regulates whereas 4-hydroxytamoxifen down-regulates VDR protein expression, indicating appropriate homologous and heterologous VDR regulation in MCF-7D3Ras cells. Gel shift analyses indicate that nuclear extracts from MCF-7WT and MCF-7D3Res cells bind equally well to the DR3 consensus vitamin D3 response element. These data suggest that MCF-7D3Res cells have a functional VDR that is uncoupled from a functional apoptotic pathway. MCF-7D3Res cells offer a unique model system for identification of the mechanisms by which vitamin D3 regulates the cell death pathway in breast cancer cells.

Characterization of a vitamin D3-resistant MCF-7 cell line.