Men of African Ancestry are primed for aggressive prostate cancer by high prostate androgens driven by vitamin D deficiency and megalin

SUMMARY African American (AA) men have twice the risk of aggressive lethal prostate cancer (PCa) and are diagnosed younger than white men. Epidemiologic studies demonstrate an increased risk of aggressive PCa with vitamin D deficiency. AA men tend to be deficient in vitamin D because melanin absorbs UV radiation, reducing sunlight- induced cutaneous vitamin D synthesis. Mounting evidence from my lab demonstrates that vitamin D deficiency alters the hormone levels of the prostate, which may contribute to the disparity of PCa observed in AA men. Our recent publications and preliminary data show that vitamin D status regulates prostate dihydrotestosterone levels, which connects these two disparities and provides a mechanism by which vitamin D affects PCa aggressiveness. We further implicate megalin as mediating the effect of vitamin D on prostate androgens. Our long-term goal is to thoroughly examine the relationship between vitamin D and androgen hormones systemically and how that may vary by ancestry. Here, we propose to examine megalin as a critical protein involved in prostate hormone regulation. The project includes three complementary, yet independent aims and the approach combines analysis of patient-derived models and mouse studies with clinical samples from AA and white men for megalin. This proposal aims to test the hypothesis that vitamin D deficiency leads to increased prostatic androgens in African American men via megalin, resulting in an increased risk of aggressive PCa. In contrast to serum levels, there is a paucity of information regarding regulation of intra-tissue levels of hormones. Given that megalin regulates prostate T levels AND that megalin is regulated by vitamin D, further understanding this mechanism will provide crucial new insight into the consequences of vitamin D deficiency which may underpin PCa disparities in African American men. New insight that directly links vitamin D status to prostate androgens has the potential to move the needle for general practitioners who would then take vitamin D deficiency seriously for African American patients. Our findings may lead to increased screening for and treatment of vitamin D deficiency, ultimately decreasing the burden of aggressive and lethal PCa in African American men.