title: Tumor Autonomous Effects of Vitamin D Deficiency Promote Breast Cancer Metastasis.
abstract: Patients with breast cancer (BCa) frequently have preexisting vitamin D deficiency (low serum 25-hydroxyvitamin D) when their cancer develops. A number of epidemiological studies show an inverse association between BCa risk and vitamin D status in humans, although some studies have failed to find an association. In addition, several studies have reported that BCa patients with vitamin D deficiency have a more aggressive molecular phenotype and worse prognostic indicators. However, it is unknown whether this association is mechanistically causative and, if so, whether it results from systemic or tumor autonomous effects of vitamin D signaling. We found that ablation of vitamin D receptor expression within BCa cells accelerates primary tumor growth and enables the development of metastases, demonstrating a tumor autonomous effect of vitamin D signaling to suppress BCa metastases. We show that vitamin D signaling inhibits the expression of the tumor progression gene Id1, and this pathway is abrogated in vitamin D deficiency in vivo in 2 murine models of BCa. These findings are relevant to humans, because we discovered that the mechanism of VDR regulation of Inhibitor of differentiation 1 (ID1) is conserved in human BCa cells, and there is a negative correlation between serum 25-hydroxyvitamin D levels and the level of ID1 in primary tumors from patients with BCa.
authors.affiliation: Department of Pediatrics (J.D.W., A.A., A.V.K., L.J., B.J.F.), Stanford School of Medicine, Stanford, California 94305; Department of Medicine (S.S.), Stanford School of Medicine, Stanford, California 94305; Department of Comparative Medicine (M.A.A.), Stanford School of Medicine, Stanford, California 94305; and Stanford Cancer Institute (B.J.F.), Stanford School of Medicine, Stanford, California 94305.
authors.forename: Jasmaine D
authors.initials: JD
authors.lastname: Williams
authors.affiliation: Department of Pediatrics (J.D.W., A.A., A.V.K., L.J., B.J.F.), Stanford School of Medicine, Stanford, California 94305; Department of Medicine (S.S.), Stanford School of Medicine, Stanford, California 94305; Department of Comparative Medicine (M.A.A.), Stanford School of Medicine, Stanford, California 94305; and Stanford Cancer Institute (B.J.F.), Stanford School of Medicine, Stanford, California 94305.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Department of Pediatrics (J.D.W., A.A., A.V.K., L.J., B.J.F.), Stanford School of Medicine, Stanford, California 94305; Department of Medicine (S.S.), Stanford School of Medicine, Stanford, California 94305; Department of Comparative Medicine (M.A.A.), Stanford School of Medicine, Stanford, California 94305; and Stanford Cancer Institute (B.J.F.), Stanford School of Medicine, Stanford, California 94305.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Swami
authors.affiliation: Department of Pediatrics (J.D.W., A.A., A.V.K., L.J., B.J.F.), Stanford School of Medicine, Stanford, California 94305; Department of Medicine (S.S.), Stanford School of Medicine, Stanford, California 94305; Department of Comparative Medicine (M.A.A.), Stanford School of Medicine, Stanford, California 94305; and Stanford Cancer Institute (B.J.F.), Stanford School of Medicine, Stanford, California 94305.
authors.forename: Aruna V
authors.initials: AV
authors.lastname: Krishnan
authors.affiliation: Department of Pediatrics (J.D.W., A.A., A.V.K., L.J., B.J.F.), Stanford School of Medicine, Stanford, California 94305; Department of Medicine (S.S.), Stanford School of Medicine, Stanford, California 94305; Department of Comparative Medicine (M.A.A.), Stanford School of Medicine, Stanford, California 94305; and Stanford Cancer Institute (B.J.F.), Stanford School of Medicine, Stanford, California 94305.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Pediatrics (J.D.W., A.A., A.V.K., L.J., B.J.F.), Stanford School of Medicine, Stanford, California 94305; Department of Medicine (S.S.), Stanford School of Medicine, Stanford, California 94305; Department of Comparative Medicine (M.A.A.), Stanford School of Medicine, Stanford, California 94305; and Stanford Cancer Institute (B.J.F.), Stanford School of Medicine, Stanford, California 94305.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Albertelli
authors.affiliation: Department of Pediatrics (J.D.W., A.A., A.V.K., L.J., B.J.F.), Stanford School of Medicine, Stanford, California 94305; Department of Medicine (S.S.), Stanford School of Medicine, Stanford, California 94305; Department of Comparative Medicine (M.A.A.), Stanford School of Medicine, Stanford, California 94305; and Stanford Cancer Institute (B.J.F.), Stanford School of Medicine, Stanford, California 94305.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Feldman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000150:complications / Q000235:genetics / Q000378:metabolism*
chemical_list: C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D018167:Receptors, Calcitriol; D014807:Vitamin D; C104450:25-hydroxyvitamin D