Abstract B079: Vitamin D metabolism is suppressed postpartum: Implications for targeting the postpartum window for cancer prevention

Abstract

Abstract Postpartum mammary gland involution is a physiologic inflammatory process that associates with increased risk of postpartum breast cancer (PPBC). Pre-clinical studies provide rationale for targeting this pro-tumor window of involution for PPBC prevention. However, the liver also undergoes physiological remodeling after weaning—consistent with weaning-induced mammary gland involution—which could potentially impact the efficacy of anti-cancer prodrugs administered during the postpartum period. Here, we used mouse models to test the efficacy of vitamin D, a prodrug with known anti-cancer properties, during the postpartum period. Vitamin D supplementation is of particular interest due to its inclusion in dietary guidelines for postpartum women, where vitamin D deficiency is prevalent. Dietary vitamin D is biologically inactive and requires hydroxylation in the liver by Cyp2r1 to produce its circulating form (25(OH)D), which is further hydroxylated in the kidneys to produce the active form (1,25(OH)2D). To understand the impact of liver involution on vitamin D hydroxylation, RNAseq was performed on livers collected from nulliparous or involution mice. Expression of Cyp2r1 was 2-fold lower in involution livers, compared to nulliparous livers (p<0.001). Further, Cyp24a1, which is responsible for degradation of active vitamin D, was increased 5.5-fold in involution livers compared to nulliparous livers (p<0.001). These findings suggest that vitamin D supplementation would be ineffective in the postpartum period. Indeed, nulliparous mice supplemented with vitamin D showed a >2-fold increase in serum 25(OH)D (67.4±8.1nmol/L) compared to nulliparous mice fed a deficient diet (28.7±11.7nmol/L, p<0.01). In contrast, supplementation of involution mice did not increase serum 25(OH)D (supplemented=46.6±8.7nmol/L, deficient=33.7±8.5nmol/L, p>0.05). In the liver, tissue-specific concentrations of 25(OH)D were lower in supplemented involution mice (1.3±0.6ng/g), compared to supplemented nulliparous mice (2.0±0.4ng/g; p=0.02). To assess whether suppression of vitamin D metabolism impacts the anti-cancer activity of dietary vitamin D, mammary cancer cells (D2A1, 2 × 104 cells) were injected into mammary fatpads of mice. In nulliparous mice, vitamin D supplementation associated with a 3-fold reduction in tumor growth (p=0.03); whereas no anti-cancer effects were observed in involution mice. These findings suggest the anti-cancer effects of vitamin D are blocked postpartum due to suppression of vitamin D metabolism in the liver. Understanding how the postpartum liver metabolizes drugs is essential for targeting treatments to this window. A retrospective analysis of our RNAseq data identified 22 additional Cytochrome P450 (CYP450) enzymes—key players in drug metabolism—whose expression was regulated by reproductive stage, suggesting that the effect of liver involution extends beyond suppressed vitamin D metabolism. These findings highlight the importance of considering the postpartum involution period in the design and administration of pharmacological interventions. Citation Format: Sarah M Bernhardt, Pepper Schedin. Vitamin D metabolism is suppressed postpartum: Implications for targeting the postpartum window for cancer prevention [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B079.