Abstract 6435: Postpartum breast cancer, liver CYP450 metabolism and drug resistance

Postpartum breast involution is a physiologic inflammatory process associated with poor-prognostic, postpartum breast cancer (PPBC). In rodent models of PPBC, weaning-induced mammary and liver involution promote- and NSAIDs mitigate-mammary tumor growth and metastasis, providing rationale for targeting weaning with anti-inflammatory agents. Vitamin D3 is an anti-inflammatory agent with a good safety profile in lactating women. Vitamin D deficiency is also prevalent postpartum, suggesting vitamin D3 supplementation may mitigate the pro-tumor inflammatory milieu associated with postpartum breast involution. To achieve vitamin D deficiency and supplementation status, adult BALB/c mice were fed diets deficient or supplemented with vitamin D3 (as nulliparous mice or during pregnancy/lactation/weaning cycle for the postpartum group). Serum vitamin D (i.e., 25(OH)D) levels, assayed in nulliparous and 2 days post-wean (involution) mice, revealed that nulliparous mice supplemented with vitamin D3 had a >2-fold increase in circulating 25(OH)D (67.4±8.1nmol/L) compared to mice fed a vitamin D3 deficient diet (28.7±11.7nmol/L, p<0.01). In contrast, involution mice fed a vitamin D3 supplemented diet did not show increased serum 25(OH)D concentrations (supplemented 46.6±8.7nmol/L vs deficient 33.7±8.5nmol/L, p>0.05). Liver concentration of 1,25(OH)2D3 was reduced 3-fold in involution group (0.31±0.29ng/g) compared to nulliparous group mice (0.90±0.37ng/g, p=0.04). Activation of dietary vitamin D requires hydroxylation within the liver, producing both circulating (25(OH)D) and active (1,25(OH)2D3) forms. Liver expression of Cyp2r1 and Cyp27b1, key liver genes involved in the synthesis of the active metabolite, 1,25(OH)2D3 were reduced post-wean, while Cyp24a1 involved in the degradation of 1,25(OH)2D3 was increased. Thus, impaired liver metabolism of vitamin D3 in the postpartum liver reduces bioavailability of active vitamin D. Seventy additional CYP450 enzymes responsible for xenobiotic metabolism clustered by reproductive stage. We next investigated how suppressed vitamin D metabolism in the postpartum liver affects the anti-cancer activity of vitamin D3 in a mouse model of PPBC. In nulliparous mice, vitamin D3 supplementation associated with anti-tumor immunity and a 3.4-fold reduction in tumor growth (p=0.03). In contrast, vitamin D3 supplementation during involution was ineffective. Importantly, when bypassing the tight regulation of active vitamin D metabolism during involution, by treating with 1,25(OH)2D3, only involution group mice became hypercalcemic, necessitating euthanasia due to kidney toxicity. These studies define an attribute of weaning-induced liver involution, transient loss of Vit D3 metabolism, with implications for responsivity to standard of care chemotherapeutics in PPBC patients. Citation Format: Sarah Bernhardt, Michelle Ozaki, Nicole Andeen, Pepper Schedin. Postpartum breast cancer, liver CYP450 metabolism and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6435.