Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model

Young women have increased risk of vitamin D deficiency, which may increase breast cancer incidence. Here, we assessed the anti-cancer efficacy of vitamin D in mouse models of young-onset breast cancer. In never-pregnant mice, vitamin D supplementation increased serum 25(OH)D and hepatic 1,25(OH) 2 D 3 , reduced tumor size, and associated with anti-tumor immunity. These anti-tumor effects were not replicated in a mouse model of postpartum breast cancer, where hepatic metabolism of vitamin D was suppressed post-wean, which resulted in deficient serum 25(OH)D and reduced hepatic 1,25(OH) 2 D 3 . Treatment with active 1,25(OH) 2 D 3 induced hypercalcemia exclusively in post-wean mice, highlighting metabolic imbalance post-wean. RNAseq revealed suppressed CYP450 expression postpartum. In sum, we provide evidence that vitamin D anti-tumor activity is mediated through immunomodulatory mechanisms and is ineffective in the post-wean window due to altered hepatic metabolism. These findings have implications for suppressed xenobiotic metabolism in postpartum women beyond vitamin D. Statement of Significance In a rodent model of postpartum breast cancer, weaning suppresses hepatic CYP450 activity and renders vitamin D supplementation ineffective, with implications for xenobiotic drug efficacy and safety. A tailored approach to therapy based on reproductive history is crucial for young breast cancer patients, and for healthcare strategies for postpartum women.