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

item ROSSDEUTSCHER, ART - McGill University - Canada
item LI, JIARONG - McGill University - Canada
item LUCO, AIMEE-LEE - McGill University - Canada
item FADHIL, IBTIHAL - McGill University - Canada
item OCHIETTI, BENOIT - McGill University - Canada
item CAMIRAND, ANNE - McGill University - Canada
item HUANG, DAO CHAO - McGill University - Canada
item Reinhardt, Timothy
item MULLER, WILLIAM - McGill University - Canada
item KREMER, RICHARD - McGill University - Canada

Submitted to: Cancer Prevention Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/24/2014
Publication Date: 2/1/2015
Publication URL:
Citation: Rossdeutscher, A., Li, J., Luco, A., Fadhil, I., Ochietti, B., Camirand, A., Huang, D., Reinhardt, T.A., Muller, W., Kremer, R. 2015. Chemoprevention activity of 25-hydroxyvitamin D in the MMTV-PyMT mouse model of breast cancer. Cancer Prevention Research. 8(2):120-128. DOI: 10.1158/1940-6207.CAPR-14-0110.

Interpretive Summary: Adequate intra-mammary Vitamin D (in the form of 25(OH)-vitamin D) has been shown to have therapeutic benefit in dairy cow mammary mastitis and to have a variety of beneficial effects for many diseases. Cellular activation of beneficial vitamin D dependent pathways is highly dependent on dietary vitamin d intake that is above official recommendations in humans. The current recommended vitamin D intake in cows meet’s the cellular requirements which is in contrast to human data. Many cancers including breast/mammary are linked to inadequate vitamin D status. This research shows that just like dairy cow mastitis, 25(OH)-vitamin D may have therapeutic benefits in the treatment of mammary cancers when provided as a therapy in a mouse breast cancer model.

Technical Abstract: Development of oncologic conditions is often linked to inadequate vitamin D status. The chemoprevention ability of this molecule is of high interest for breast cancer, the most common malignancy in women worldwide. Current effective vitamin D analogs including the naturally occurring active metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D) frequently cause hypercalcemia at pharmacological doses, and the development of safer molecules for clinical chemopreventive use is therefore essential. The present study examines whether 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 MMTVPyMT 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 but importantly, in contrast to 1,25(OH)2D, 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. This study indicates that exogenous 25(OH)D can be converted into active 1,25(OH)2D within breast tumor cells and plays a significant role in delaying neoplasia, tumor growth and metastasis without inducing detrimental hypercalcemic effects such as caused by 1,25(OH)2D. These observations suggest potential chemoprevention utility for the 25(OH)D metabolite.