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Proposal

Breast cancer remains the second leading cause of cancer death among women in the United States, with 99% of breast cancer patients surviving fi ve years after diagnosis if the tumor is localized. However, if the tumor has metastasized, the survival rate decreases to 22%. Epidemiological and animal studies, as well as previous studies from our laboratory in in vitro 3D cell culture models, support the hypothesis that vitamin D may inhibit breast cancer metastasis in humans, but the mechanisms remain unknown. The purpose of the present studies was to investigate the effect of the bioactive vitamin D metabolite, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) on expression of matrix metalloproteinases (MMP) in MCF10CA1a breast epithelial cells. MMPs are a family of endopeptidases implicated in both cancer cell invasion and migration. First, the pattern of MMP expression in MCF10CA1a cells was investigated, focusing on MMPs 1,2,3,9 and 13. MCF10CA1a cells expressed only MMP2 mRNA at a detectable level. Treatment with 1,25(OH)2D (10 nM,) reduced the expression of MMP2 by 32%±10 and 35%±7 at 2 and 5 days, respectively. Furthermore, the effect of 1,25(OH)2D on migratory capability of MCF10CA1a cells was assessed using a wound healing assay. Pretreatment with 1,25(OH)2D for 48 hours decreased cell migration by 44%±9.6 relative to vehicle. Overall, these studies support a potential role of MMP2 and migration in 1,25(OH)2D prevention of breast cancer metastasis.

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