Chemoprevention activity of 25-hydroxyvitamin D in the MMTV-PyMT mouse model of breast cancer.

Lionel Rossdeutscher,Ibtihal Fadhil,Jiarong Li,Benoit Ochietti,Aimée-Lee Luco,Richard Kremer,Dao Chao Huang,Anne Camirand,William Muller,Timothy A Reinhardt

doi:10.1158/1940-6207.capr-14-0110

Abstract

Development of oncologic conditions is often accompanied by inadequate vitamin D status. The chemoprevention ability of this molecule is of high interest for breast cancer, the most common malignancy in women worldwide. Because current effective vitamin D analogues, including the naturally occurring active metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D), frequently cause hypercalcemia at pharmacologic doses, the development of safer molecules for clinical chemopreventive use is essential. This study examines whether exogenously supplied prohormone 25-hydroxycholecalciferol (25(OH)D) can delay tumor progression in vivo without hypercalcemic effects. A low vitamin D diet (25 IU/kg) in the non-immunodeficient MMTV-PyMT mouse model of metastatic breast cancer revealed a significant acceleration of mammary neoplasia compared with normal diet (1,000 IU/kg). Systemic perfusion of MMTV-PyMT mice with 25(OH)D or 1,25(OH)2D delayed tumor appearance and significantly decreased lung metastasis, and both metabolites reduced Ki-67, cyclin D1, and ErbB2 levels in tumors. Perfusion with 25(OH)D caused a 50% raise in tumor 1,25(OH)2D levels, indicating good tumor penetration and effective activation. Importantly, in contrast with 1,25(OH)2D, perfusion with 25(OH)D did not cause hypercalcemia. In vitro treatment of cultured MMTV-PyMT mammary tumor cells with 25(OH)D inhibited proliferation, confirming local activation of the prohormone in this system. This study provides an in vivo demonstration in a non-immunodeficient model of spontaneous breast cancer that exogenous 25(OH)D delays neoplasia, tumor growth, and metastasis, and that its chemoprevention efficacy is not accompanied by hypercalcemia.

Highlights

Breast cancer is the most common malignancy in women worldwide, with more than 220,000 new cases reported in the United States alone in 2012, and is the second leading cause of female cancer-related death [1]
Using the MMTV-polyoma middle T antigen (PyMT) model, we show that that exogenous 25(OH)D activated into 1,25(OH)2D within breast tumor cells delays neoplasia, tumor growth, and metastasis without inducing detrimental hypercalcemic effects
After 6 weeks of treatment, blood 25 (OH)D levels in low vitamin D mice were only 18% of those in vitamin D-replete mice (Fig. 1A) and animals on the low vitamin D diet exhibited a significantly faster onset of spontaneous mammary gland hyperplasia (Fig. 1B and C). These data show that dietary vitamin D insufficiency accelerates the appearance and progression of mammary tumors in this immunocompetent oncogene-driven breast cancer model

Summary

Introduction

Breast cancer is the most common malignancy in women worldwide, with more than 220,000 new cases reported in the United States alone in 2012, and is the second leading cause of female cancer-related death [1]. The discovery of novel and effective chemopreventive agents for people at higher risk of developing mammary malignancies could help reduce cancer appearance or delay its progression. Among several agents under study, the biologically active form and analogues of vitamin D appear promising due to their antiproliferative, prodifferentiating, anti-inflammatory, and immunomodulatory activities [2]. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

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