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Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):E2186-E2194. doi: 10.1073/pnas.1615015114. Epub 2017 Feb 27.

Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells.

Author information

1
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
2
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
3
Santa Fe Institute, Santa Fe, NM 87501.
4
Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, University of South Florida, Tampa, FL 33612.
5
Institut National de la Recherche Scientifique, Centre Énergie, Matériaux, Télécommunications, University of Quebec, Montreal, QC H5A 1K6, Canada.
6
Confocal and Light Microscopy Core, Dana-Farber Cancer Institute, Boston, MA 02215.
7
Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215.
8
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
9
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.

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.

KEYWORDS:

autophagy; breast cancer; oncology; vitamin D; vitamin D signaling

PMID:
28242709
PMCID:
PMC5358377
DOI:
10.1073/pnas.1615015114
[Indexed for MEDLINE]
Free PMC Article

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