CCAAT enhancer-binding protein α is a molecular target of 1,25-dihydroxyvitamin D3 in MCF-7 breast cancer cells

Abstract

Numerous studies have shown that the active form of vitamin D, 1,25(OH)2D3, can exert growth inhibitory effects on human breast cancer cells and mammary tumor growth. However, the molecular mechanisms remain to be fully delineated. This study demonstrates for the first time that CCAAT enhancer-binding protein α (C/EBPα), a member of the C/EBP family of transcription factors, is induced by 1,25(OH)2D3 and is a potent enhancer of VDR transcription in MCF-7 breast cancer cells. 1,25(OH)2D3 was found to induce C/EBPα as well as VDR expression in MCF-7 cells. C/EBPα was not detected in MDA-MB-231 cells that are poorly responsive to 1,25(OH)2D3. Antiproliferative effects of 1,25(OH)2D3 and induction of VDR were observed in MDA-MB-231 cells transfected with C/EBPα, and knockdown of C/EBPα suppressed VDR and antiproliferative effects of 1,25(OH)2D3 in MCF-7 cells. Transfection of C/EBPα in MCF-7 cells resulted in a dose-dependent enhancement of hVDR transcription. Our studies show that C/EBPα can bind to Brahma (Brm), an ATPase that is a component of the SWI/SNF complex, and cooperate with Brm in the regulation of hVDR transcription in MCF-7 cells. Because the levels of VDR in MCF-7 breast cancer cells correlate with the antiproliferative effects of 1,25(OH) 2D3 and because C/EBPα has been suggested as a potential tumor suppressor in breast cancer, these findings provide important mechanisms whereby 1,25(OH)2D3 may act to inhibit growth of breast cancer cells. These findings also identify C/EBPα as a 1,25(OH)2D3 target in breast cancer cells and provide evidence for C/EBPα as a candidate for breast cancer treatment. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.