Luz E. Tavera-Mendoza, Thomas Westerling, Eric Libby, Andriy Marusyk, Laura Cato, Raymundo Cassani, Lisa A. Cameron, Scott B. Ficarro, Jarrod A. Marto, Jelena Klawitter, and Myles Brown
Significance
Epidemiological evidence suggests that vitamin D can protect women from developing breast cancer (BC). This study reveals that vitamin D and its receptor regulate autophagy in both normal mammary epithelial cells and luminal BCs, and suggests a potential mechanism underlying the link between vitamin D levels and BC risk. In addition, this work suggests that vitamin D receptor ligands could be exploited therapeutically for the treatment of a significant subset of BCs.
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.
See http://www.pnas.org/content/114/11/E2186.full
PNAS March 14 2017; vol.114; no.11: E2186–E2194
Fig. 1.
Vitamin D increases the acid compartments and inhibits proliferation specifically in luminal-like BC cells. (A) Cell counts of luminal-like and nonluminal-like BC-cell lines with 10 nM, 100 nM, and 1 μM 1,25(OH)2D3. *P ≤ 0.05 and **P ≤ 0.01 as determined by one-way ANOVA. (B) LysoTracker Red staining of live luminal and nonluminal cell lines. (Magnification: 20×.) The positive control is 8 h of serum starvation, the negative control is carrier control, and treatment is 5 d of 100 nM 1,25(OH)2D3. ctrl, control.
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