Abstract
Numerous studies have shown that the active form of vitamin D, 1,25(OH)(2)D-3, 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 alpha(C/EBP alpha), a member of the C/EBP family of transcription factors, is induced by 1,25(OH)(2)D-3 and is a potent enhancer of VDR transcription in MCF-7 breast cancer cells. 1,25(OH)(2)D-3 was found to induce C/EBP alpha as well as VDR expression in MCF-7 cells. C/EBP alpha was not detected in MDA-MB-231 cells that are poorly responsive to 1,25(OH)(2)D-3. Antiproliferative effects of 1,25(OH)(2)D-3 and induction of VDR were observed in MDA-MB-231 cells transfected with C/EBP alpha, and knockdown of C/EBP alpha suppressed VDR and antiproliferative effects of 1,25(OH)(2)D-3 in MCF-7 cells. Transfection of C/EBP alpha in MCF-7 cells resulted in a dose-dependent enhancement of hVDR transcription. Our studies show that C/EBP alpha 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)(2)D-3 and because C/EBP alpha has been suggested as a potential tumor suppressor in breast cancer, these findings provide important mechanisms whereby 1,25(OH)(2)D-3 may act to inhibit growth of breast cancer cells. These findings also identify C/EBP alpha as a 1,25(OH)(2)D-3 target in breast cancer cells and provide evidence for C/EBP alpha as a candidate for breast cancer treatment.