Abstract 4231: The anti-cancer effects of vitamin D are blocked postpartum due to suppression of vitamin D metabolism in the liver
Authors: Bernhardt Sarah M. , Schedin Pepper 
Published: April 2023

Abstract
Postpartum breast involution is a physiologic inflammatory process that associates with increased risk of postpartum breast cancer (PPBC). In rodents, involution promotes breast cancer progression, and treatment with anti-inflammatory agents is protective. These data provide rationale for targeting the pro-tumor window of involution with anti-inflammatory agents for PPBC prevention. Vitamin D is another anti-inflammatory agent with a good safety profile. In postpartum women, vitamin D deficiency is prevalent, suggesting vitamin D supplementation during involution may prevent development of PPBC.
To model vitamin D deficiency and supplementation, BALB/c mice were fed diets deficient or supplemented with vitamin D for 4 weeks. Blood was then collected from nulliparous (never-pregnant) and 2 days post-wean (involution) mice, and serum vitamin D (i.e. 25(OH)D) measured. As expected, nulliparous mice fed a vitamin D supplemented diet showed a &gt;2-fold increase in serum 25(OH)D (67.4±8.1nmol/L) compared to mice fed a vitamin D deficient diet (28.7±11.7nmol/L, p&lt;0.01). In contrast, involution mice fed a vitamin D supplemented diet did not show increased serum 25(OH)D (supplemented 46.6±8.7nmol/L vs deficient 33.7±8.5nmol/L, p&gt;0.05).
Activation of dietary vitamin D requires hydroxylation in the liver, producing both circulating (25(OH)D) and active (1,25(OH)2D) forms. Thus, reduced serum 25(OH)D in vitamin D supplemented involution mice could be due to impaired vitamin D hydroxylation in the post-wean liver. Analysis of livers collected from involution and nulliparous mice found reduced expression of genes involved in vitamin D hydroxylation (Cyp2r1, Cyp27a1) during involution. Further, liver concentrations of 1,25(OH)2D were reduced 3-fold in involution mice (0.31±0.29ng/g) compared to nulliparous mice (0.90±0.37ng/g, p=0.04). Together, these findings suggest that impaired metabolism of vitamin D in the postpartum liver may reduce bioavailability of active vitamin D, and provide corroborative evidence for weaning-induced liver involution.
To understand how suppressed vitamin D metabolism in the postpartum liver affects the anti-cancer activity of dietary vitamin D, mammary cancer cells (D2A1, 2 × 104 cells, 20µL) were injected into mammary fatpad of involution or nulliparous BALB/c mice, and tumor growth tracked for 4 weeks. 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. Together, these findings suggest the anti-cancer effects of vitamin D are blocked postpartum, likely due to suppression of vitamin D metabolism in the liver. Understanding how postpartum liver metabolism influences efficacy of preventative agents that require liver metabolism (such as vitamin D) is required to optimize cancer prevention strategies that target this window.
Citation Format: Sarah M. Bernhardt, Pepper Schedin. The anti-cancer effects of vitamin D are blocked postpartum due to suppression of vitamin D metabolism in the liver. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4231.