Identification of vitamin D3 target genes in human breast cancer tissue. Issue 164 (November 2016)

• Record Type: Journal Article
• Authors: Sheng, Lei; Anderson, Paul H.; Turner, Andrew G.; Pishas, Kathleen I.; Dhatrak, Deepak J.; Gill, Peter G.; Morris, Howard A.; Callen, David F.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 164(2016)
• Page Start: 90
• Page End: 97
• Publication Date: 2016-11
• Subjects: Vitamin D3 -- RNA-Seq -- Mammary tissue -- Genomics -- Breast cancer; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2015.10.012
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: 1, 25D-mediated target genes and pathways were identified in human breast explants. Inhibition of CYP24A1 activity may enhance the antitumor effect of 1, 25D. Up-regulation of three 1, 25D targets predicts prolonged relapse-free survival. Our data agree with evidence that high 25D levels improve breast cancer outcome. Abstract: Multiple epidemiological studies have shown that high vitamin D3 status is strongly associated with improved breast cancer survival. To determine the molecular pathways influenced by 1 alpha, 25-dihydroxyvitamin D3 (1, 25D) in breast epithelial cells we isolated RNA from normal human breast and cancer tissues treated with 1, 25D in an ex vivo explant system. RNA-Seq revealed 523 genes that were differentially expressed in breast cancer tissues in response to 1, 25D treatment, and 127 genes with altered expression in normal breast tissues. GoSeq KEGG pathway analysis revealed 1, 25D down-regulated cellular metabolic pathways and enriched pathways involved with intercellular adhesion. The highly 1, 25D up-regulated target genes CLMN, SERPINB1, EFTUD1, and KLK6 were selected for further analysis and up-regulation by 1, 25D was confirmed by qRT-PCR analysis in breast cancer cell lines and in a subset of human clinical samples from normal and cancer breast tissues. Ketoconazole potentiated 1, 25D-mediated induction of CLMN, SERPINB1, and KLK6 mRNA through inhibition of 24-hydroxylase (CYP24A1) activity. Elevated expression levels of CLMN, SERPINB1, and KLK6 are associated with prolonged relapse-free survival for breast cancer patients. The major finding of the present study is that exposure of both normal and malignant breast tissue to 1, 25D results in changes in cellular adhesion, metabolic pathways and tumor suppressor-like pathways, which support epidemiological data suggesting that adequate vitamin D3 levels may improve breast cancer outcome.