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 analogs including the naturally-occurring active metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D) frequently cause hypercalcemia at pharmacological doses, the development of safer molecules for clinical chemopreventive use is essential. The present study examines whether exogenously-supplied pro-hormone 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 (1000 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 to 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.
- Received April 4, 2014.
- Revision received October 21, 2014.
- Accepted November 6, 2014.
- Copyright © 2014, American Association for Cancer Research.