Editors' ChoiceCancer

Autophagy and vitamin D

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Science Signaling  21 Mar 2017:
Vol. 10, Issue 471, eaan2526
DOI: 10.1126/scisignal.aan2526

Vitamin D receptor represses basal autophagy in breast tissue, which is derepressed by vitamin D, slowing cancer progression.

Epidemiological evidence suggests that there is an association between higher circulating vitamin D concentration and decreased breast cancer risk, and in vitro studies suggest that vitamin D has an antiproliferative effect on certain cancers. The biologically active hormone form of vitamin D, 1,25(OH2)D3, interacts with the vitamin D receptor (VDR), a nuclear receptor and transcription factor, which is expressed in diverse tissues and has many gene targets. Tavera-Mendoza et al. found that the protective effect of vitamin D against breast cancer was attributable to its modulation of the VDR, which controlled autophagy in luminal-type breast cancer cells and healthy breast tissue in mice. In vitro, 1,25(OH2)D3 limited the proliferation of cells of the luminal A and B breast cancer subtypes (which make up 50 to 60% of breast cancer cases) but not that of cells of other breast cancer subtypes. Cells whose proliferation was inhibited by the hormone showed signs of increased autophagy, which was confirmed with lysosome tracking experiments and by detection of autophagy markers. Supplementing the diets of healthy mice with additional vitamin D increased autophagy in mammary tissue, and examination of transcriptomic data from The Cancer Genome Atlas showed that the basal expression of autophagy-related genes is greater in healthy human mammary tissue than in luminal breast cancer tissue. In mice with breast cancer cell xenografts, treatment with vitamin D in combination with chloroquine (which inhibits autophagosome degradation) substantially decreased the size of the xenograft. In VDR-deficient mice, autophagy was induced to an even greater extent than that induced by 1,25(OH2)D3 in wild-type mice, and treatment with 1,25(OH2)D3 had no additional effect, suggesting that VDR constitutively represses autophagy, which is partially derepressed by vitamin D. ChIP-seq analysis of luminal breast cancer cells confirmed that VDR bound to the gene encoding LC3B, an essential protein for autophagy, and that 1,25(OH2)D3 activated gene transcription. These results suggest that the ligand-bound VDR promotes autophagy in breast tissue and that this regulation inhibits the progression of certain cancers.

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