Research Papers:

Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and for growth inhibition of breast cancer cells and cancer stem-like cells.

Itay Pickholtz _, Shira Saadyan, Gilmor I. Keshet, Victor S. Wang, Rachel Cohen, Peter Bouwman, Jos Jonkers, Stephen W. Byers, Moshe Z. Papa and Ronit I. Yarden

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Oncotarget. 2014; 5:11827-11846. https://doi.org/10.18632/oncotarget.2582

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Itay Pickholtz1,2,3,*, Shira Saadyan1, Gilmor I. Keshet2, Victor S. Wang4, Rachel Cohen1, Peter Bouwman5, Jos Jonkers5, Stephen W. Byers6, Moshe Z. Papa1,3, Ronit I. Yarden1,2,4,6

1Laboratory of Genomic Applications, Department of Surgical Oncology, Sheba Medical Center, Ramat-Gan 52621, Israel

2Sheba Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel

3Sackler school of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

4Department of Human Science, Georgetown University Medical Center, Washington DC 20057, USA

5Division of Molecular Pathology and Cancer Genomic Center, The Netherland Cancer Institute, Amsterdam 1066, The Netherlands

6Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW Washington DC 20057, USA

*This work was performed in partial fulfillment of the requirements for the Ph.D. degree of Itay Pickholtz, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Correspondence to:

Ronit I. Yarden, e-mail: [email protected]

Keywords: vitamin D, BRCA1, vitamin D receptor, p21waf1, breast cancer, stem cells, histone acetylation

Received: August 09, 2014     Accepted: October 09, 2014     Published: November 26, 2014


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.

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