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Breast Cancer risk reduced (in mice) which got vitamin D – May 2015

Inhibition of Mouse Breast Tumor Initiating Cells by Calcitriol and Dietary Vitamin D.

Mol Cancer Ther. 2015 May 1. pii: molcanther.0066.2015. [Epub ahead of print]
Jeong Y 1, Swami S 2, Krishnan AV 3, Williams JD 4, Martin S 5, Horst RL 6, Albertelli MA 7, Feldman BJ 4, Feldman D 3, Diehn M 8.
1Radiation Oncology, Stanford University.
2Medicine / Endocrinology, Stanford University.
3Medicine/Endocrinology, Stanford University School of Medicine.
4Department of Pediatrics/Endocrinology, Stanford University.
5Stanford Cancer Institute, Stanford University.
6Heartland Assays, Inc.
7Department of Comparative Medicine, Stanford University.
8Radiation Oncology, Stanford University diehn at stanford.edu.

The anti-cancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and pre-clinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated.

We confirmed that these tumors expressed functional vitamin D receptors (VDRs) and estrogen receptors (ERs) and exhibited calcitriol-induced molecular responses including ER down-regulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D-supplemented diet caused a striking delay in tumor appearance and growth while a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model.

Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity.

Our data also suggest that combining vitamin D compounds with standard therapies will enhance anti-cancer activity and may improve therapeutic outcomes.

Copyright © 2015, American Association for Cancer Research, PMID: 25934710

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