title: Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and growth inhibition of breast cancer cells and cancer stem-like cells.
abstract: Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression. The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is a potent inhibitor of breast cancer growth. Here we report that two non-calcemic analogues of 1α,25-dihydroxyvitamin D3, seocalcitol (EB1089) and QW-1624F2-2, collaborate with BRCA1 in mediating growth inhibition of breast cancer cells and breast cancer stem-like cells. EB1089 induces a G1/S phase growth arrest that coincides with induction of p21waf1 expression only in BRCA1-expressing cells. A complete knockdown of BRCA1 or p21waf1 renders the cells unresponsive to EB1089. Furthermore, we show that in the presence of ligand, BRCA1 associates with vitamin D receptor (VDR) and the complex co-occupies vitamin D responsive elements (VDRE) at the CDKN1A (p21waf1) promoter and enhances acetylation of histone H3 and H4 at these sites. Thus, BRCA1 expression is critical for mediating the biological impact of vitamin D3 in breast tumor cells.
authors.affiliation: Laboratory of Genomic Applications, Department of Surgical Oncology, Sheba Medical Center, Ramat-Gan 52621, Israel. Sheba Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel. Sackler school of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Itay
authors.initials: I
authors.lastname: Pickholtz
authors.affiliation: Laboratory of Genomic Applications, Department of Surgical Oncology, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Saadyan
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Gilmor I
authors.initials: GI
authors.lastname: Keshet
authors.affiliation: Department of Human Science, Georgetown University Medical Center, Washington DC 20057, USA.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Wang
authors.affiliation: Laboratory of Genomic Applications, Department of Surgical Oncology, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Division of Molecular Pathology and Cancer Genomic Center, The Netherland Cancer Institute, Amsterdam 1066, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.affiliation: Division of Molecular Pathology and Cancer Genomic Center, The Netherland Cancer Institute, Amsterdam 1066, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW Washington DC 20057, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Byers
authors.affiliation: Laboratory of Genomic Applications, Department of Surgical Oncology, Sheba Medical Center, Ramat-Gan 52621, Israel. Sackler school of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Moshe Z
authors.initials: MZ
authors.lastname: Papa
authors.affiliation: Laboratory of Genomic Applications, Department of Surgical Oncology, Sheba Medical Center, Ramat-Gan 52621, Israel. Sheba Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel. Department of Human Science, Georgetown University Medical Center, Washington DC 20057, USA. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW Washington DC 20057, USA.
authors.forename: Ronit I
authors.initials: RI
authors.lastname: Yarden
mesh_terms: D000107:Acetylation; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002762:Cholecalciferol / Q000378:metabolism* / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018167:Receptors, Calcitriol / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D018167:Receptors, Calcitriol; D002762:Cholecalciferol