The Free Hormone Hypothesis and Ancestry-related Differences in Prostate Vitamin D Uptake and Metabolism

Prostate cancer is the leading cause of cancer-related deaths in men and 1 in 7 men will be diagnosed in their lifetime. African American men are disproportionately at risk for prostate cancer and have twice the mortality compared to Caucasian men. African American men are also at increased risk of vitamin D deficiency as higher levels of skin melanin inhibit cutaneous UV penetration required for vitamin D synthesis. Vitamin D is a chemoprotective hormone that has anti-cancer actions in the prostate and deficiency has been hypothesized to contribute to the prostate cancer disparity in African American men, however, associations between vitamin D status and cancer outcomes are limited to serum assessment of vitamin D status. This thesis challenges the concept of vitamin D status by exploring intra-prostatic vitamin D metabolites and presents an ancestry-specific role for megalin-mediated endocytosis of both vitamin D and androgens in the prostate.