title: Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells.
abstract: Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic transcriptional signature in BC cells that correlates with increased survival in patients; strikingly, this signature is present in the normal mammary gland and is progressively lost in patients with metastatic BC. A number of epidemiological studies have shown that sufficient vitamin D serum levels might be protective against BC. We observed that dietary vitamin D supplementation in mice increases basal levels of autophagy in the normal mammary gland, highlighting the potential of vitamin D as a cancer-preventive agent. These findings point to a role of vitamin D and the VDR in modulating autophagy and cell death in both the normal mammary gland and BC cells.
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Luz E
authors.initials: LE
authors.lastname: Tavera-Mendoza
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Thomas
authors.initials: T
authors.lastname: Westerling
authors.affiliation: Santa Fe Institute, Santa Fe, NM 87501.
authors.forename: Eric
authors.initials: E
authors.lastname: Libby
authors.affiliation: Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, University of South Florida, Tampa, FL 33612.
authors.forename: Andriy
authors.initials: A
authors.lastname: Marusyk
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Laura
authors.initials: L
authors.lastname: Cato
authors.affiliation: Institut National de la Recherche Scientifique, Centre Énergie, Matériaux, Télécommunications, University of Quebec, Montreal, QC H5A 1K6, Canada.
authors.forename: Raymundo
authors.initials: R
authors.lastname: Cassani
authors.affiliation: Confocal and Light Microscopy Core, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cameron
authors.affiliation: Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.affiliation: Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; myles_brown@dfci.harvard.edu.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites; D015415:Biomarkers; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D064593:Heterografts; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008954:Models, Biological; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D018167:Receptors, Calcitriol; D014807:Vitamin D
keywords: autophagy; breast cancer; oncology; vitamin D; vitamin D signaling