Investigating the Role of Vitamin D in Epithelial Differentiation of the Prostate

This thesis presents the extensive impact of vitamin D on epithelial differentiation in the prostate. Utilizing three complementary models, mouse dorsolateral prostate organoids treated with vitamin D, analysis of prostates from mice with systemic vitamin D deficiency or sufficiency, and human prostate cancer cells adapted for 6 months to physiological levels of vitamin D, we demonstrate the influential role that vitamin D sufficiency plays in supporting epithelial differentiation thus benefiting healthy, benign prostatic differentiation. In the context of prostate disease, we observed substantial alterations in growth, cellular morphology, and gene expression supporting that vitamin D deficiency abrogates epithelial differentiation in prostate cancer cells thus enhancing disease aggressiveness. This work also demonstrates the complex interplay, or hormonal crosstalk, between vitamin D and androgen signaling in the prostate, extending previous findings from cell lines to three novel models and validating the importance that vitamin D plays in regulating prostatic epithelial differentiation. Overall, this thesis provides insight and validation of the beneficial, protective role of vitamin D in both benign and malignant prostate biology, highlighting the potential implications of vitamin D for therapeutic strategies, including vitamin D supplementation aimed at reducing PCa incidence and aggressiveness in at-risk populations. This thesis presents a putative relationship between the racial disparities observed in prostate cancer and vitamin D deficiency, thereby motivating future research to investigate potential mechanisms, surrounding vitamin D regulation of androgen-regulated genes, and public health implications.