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Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements.
Endocr Relat Cancer 2013; 20(4):565-77ER

Abstract

Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, exerts its anti-proliferative activity in breast cancer (BCa) cells by multiple mechanisms including the downregulation of the expression of estrogen receptor α (ER). We analyzed an ∼3.5 kb ER promoter sequence and demonstrated the presence of two potential negative vitamin D response elements (nVDREs), a newly identified putative nVDRE upstream at -2488 to -2473 bp (distal nVDRE) and a previously published sequence (proximal nVDRE) at -94 to -70 bp proximal to the P1 start site. Transactivation analysis using ER promoter deletion constructs and heterologous promoter-reporter constructs revealed that both nVDREs functioned to mediate calcitriol transrepression. In the electrophoretic mobility shift assay, the vitamin D receptor (VDR) showed strong binding to both nVDREs in the presence of calcitriol, and the chromatin immunoprecipitation assay demonstrated the recruitment of the VDR to the distal nVDRE site. Mutations in the 5' hexameric DNA sequence of the distal nVDRE resulted in the loss of calcitriol-mediated transrepression and the inhibition of protein-DNA complex formation, demonstrating the importance of these nucleotides in VDR DNA binding and transrepression. A putative nuclear factor-Y (NFY) binding site, identified within the distal nVDRE, led to the findings that NFY bound to the distal nVDRE site interfered with the binding of the VDR at the site and reduced calcitriol-mediated transrepression. In conclusion, the ER promoter region contains two negative VDREs that act in concert to bind to the VDR and both nVDREs are required for the maximal inhibition of ER expression by calcitriol. The suppression of ER expression and estrogen-mediated signaling by calcitriol in BCa cells suggests that vitamin D may be useful in the treatment of ER+ BCa.

Authors+Show Affiliations

Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5103, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23744764

Citation

Swami, Srilatha, et al. "Transrepression of the Estrogen Receptor Promoter By Calcitriol in Human Breast Cancer Cells Via Two Negative Vitamin D Response Elements." Endocrine-related Cancer, vol. 20, no. 4, 2013, pp. 565-77.
Swami S, Krishnan AV, Peng L, et al. Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements. Endocr Relat Cancer. 2013;20(4):565-77.
Swami, S., Krishnan, A. V., Peng, L., Lundqvist, J., & Feldman, D. (2013). Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements. Endocrine-related Cancer, 20(4), pp. 565-77. doi:10.1530/ERC-12-0281.
Swami S, et al. Transrepression of the Estrogen Receptor Promoter By Calcitriol in Human Breast Cancer Cells Via Two Negative Vitamin D Response Elements. Endocr Relat Cancer. 2013;20(4):565-77. PubMed PMID: 23744764.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements. AU - Swami,Srilatha, AU - Krishnan,Aruna V, AU - Peng,Lihong, AU - Lundqvist,Johan, AU - Feldman,David, Y1 - 2013/07/05/ PY - 2013/6/8/entrez PY - 2013/6/8/pubmed PY - 2014/1/25/medline KW - breast cancer cells KW - calcitriol KW - estrogen receptor KW - estrogen signaling KW - nVDREs KW - transrepression KW - vitamin D SP - 565 EP - 77 JF - Endocrine-related cancer JO - Endocr. Relat. Cancer VL - 20 IS - 4 N2 - Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, exerts its anti-proliferative activity in breast cancer (BCa) cells by multiple mechanisms including the downregulation of the expression of estrogen receptor α (ER). We analyzed an ∼3.5 kb ER promoter sequence and demonstrated the presence of two potential negative vitamin D response elements (nVDREs), a newly identified putative nVDRE upstream at -2488 to -2473 bp (distal nVDRE) and a previously published sequence (proximal nVDRE) at -94 to -70 bp proximal to the P1 start site. Transactivation analysis using ER promoter deletion constructs and heterologous promoter-reporter constructs revealed that both nVDREs functioned to mediate calcitriol transrepression. In the electrophoretic mobility shift assay, the vitamin D receptor (VDR) showed strong binding to both nVDREs in the presence of calcitriol, and the chromatin immunoprecipitation assay demonstrated the recruitment of the VDR to the distal nVDRE site. Mutations in the 5' hexameric DNA sequence of the distal nVDRE resulted in the loss of calcitriol-mediated transrepression and the inhibition of protein-DNA complex formation, demonstrating the importance of these nucleotides in VDR DNA binding and transrepression. A putative nuclear factor-Y (NFY) binding site, identified within the distal nVDRE, led to the findings that NFY bound to the distal nVDRE site interfered with the binding of the VDR at the site and reduced calcitriol-mediated transrepression. In conclusion, the ER promoter region contains two negative VDREs that act in concert to bind to the VDR and both nVDREs are required for the maximal inhibition of ER expression by calcitriol. The suppression of ER expression and estrogen-mediated signaling by calcitriol in BCa cells suggests that vitamin D may be useful in the treatment of ER+ BCa. SN - 1479-6821 UR - https://www.unboundmedicine.com/medline/citation/23744764/Transrepression_of_the_estrogen_receptor_promoter_by_calcitriol_in_human_breast_cancer_cells_via_two_negative_vitamin_D_response_elements_ L2 - https://erc.bioscientifica.com/doi/10.1530/ERC-12-0281 DB - PRIME DP - Unbound Medicine ER -