CCAAT enhancer-binding protein alpha is a molecular target of 1,25-dihydroxyvitamin D3 in MCF-7 breast cancer cells.
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/EBPalpha), 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/EBPalpha as well as VDR expression in MCF-7 cells. C/EBPalpha 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/EBPalpha, and knockdown of C/EBPalpha suppressed VDR and antiproliferative effects of 1,25(OH)(2)D(3) in MCF-7 cells. Transfection of C/EBPalpha in MCF-7 cells resulted in a dose-dependent enhancement of hVDR transcription. Our studies show that C/EBPalpha 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/EBPalpha 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/EBPalpha as a 1,25(OH)(2)D(3) target in breast cancer cells and provide evidence for C/EBPalpha as a candidate for breast cancer treatment.
Dhawan
Puneet
P
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103.
Wieder
Robert
R
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103.
Christakos
Sylvia
S
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103. Electronic address: christak@umdnj.edu.
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism* / Q000502:physiology; D002117:Calcitriol / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D047468:Immunoprecipitation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology
D022763:CCAAT-Enhancer-Binding Protein-alpha; D017931:DNA Primers; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D002117:Calcitriol