title: Chemoprevention activity of 25-hydroxyvitamin D in the MMTV-PyMT mouse model of breast cancer.
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.
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Lionel
authors.initials: L
authors.lastname: Rossdeutscher
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Jiarong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Aimée-Lee
authors.initials: AL
authors.lastname: Luco
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Ibtihal
authors.initials: I
authors.lastname: Fadhil
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Ochietti
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Camirand
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Dao Chao
authors.initials: DC
authors.lastname: Huang
authors.affiliation: United States Dept of Agriculture (ARS), National Animal Disease Center, Ames, Iowa.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Reinhardt
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Muller
authors.affiliation: Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada. richard.kremer@mcgill.ca.
authors.forename: Richard
authors.initials: R
authors.lastname: Kremer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018890:Chemoprevention / Q000379:methods*; D005260:Female; D005434:Flow Cytometry; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D014808:Vitamin D Deficiency / Q000150:complications
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D