Chemoprevention Activity of 25-Hydroxyvitamin D in the MMTV-PyMT Mouse Model of Breast Cancer

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 25hydroxycholecalciferol (25(OH) D) can delay tumor progression in vivo without hypercalcemic effects. A lowvitaminDdiet (25 IU/kg) in the non-immunodeficient MMTV-PyMT mouse model of metastatic breast cancer revealed a significant acceleration ofmammary 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 lungmetastasis, 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 culturedMMTV-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-immunodeficientmodel 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. (C) 2014 AACR.