BACKGROUND. African American (AA) men are disproportionately affected by both prostate cancer (PCa) and vitamin D deficiency compared with European American (EA) men. Vitamin D deficiency is linked to increased PCa aggressiveness and mortality. Therefore, it has been hypothesized that vitamin D deficiency may contribute to the PCa disparity between AA and EA men.
METHODS. We studied a cross sectional group of 60 PCa patients (AA, n = 31; EA, n = 29) who underwent radical prostatectomy. Vitamin D metabolites 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in the serum and tissue by uHPLC-MS-MS. Tissue was laser capture microdissected, and gene expression was quantified by microarray. DNA isolated from whole blood was genotyped for West African ancestry markers and vitamin D–related SNPs.
RESULTS. Serum concentrations of 25(OH)D were lower in AAs, but concentrations of 1,25(OH)2D in the prostate tissue were higher compared with EAs. Expression of the vitamin D receptor was higher in prostate tissue from AAs. Expression of the extracellular receptor of vitamin D binding protein, LRP2, was positively associated with West African ancestry and inversely associated with tissue 25(OH)D concentrations in AAs.
CONCLUSIONS. The relationships between vitamin D binding protein LRP2 and vitamin D metabolites suggest that the prohormone is actively transported into the prostate, followed by intraprostatic conversion to the active hormone, rather than passive diffusion. These findings support the presence of a compensatory response in prostate tissue to vitamin D deficiency in AAs and reveal a previously unknown complexity involving tissue distribution of vitamin D metabolites.
FUNDING. Department of Defense Prostate Cancer Research Program Idea Award for Disparities Research PC121923 (LN and RK) and the NIH 1R01MD007105 (RK).
Zachary Richards, Ken Batai, Rachael Farhat, Ebony Shah, Andrew Makowski, Peter H. Gann, Rick Kittles, Larisa Nonn
Affymetrix array expression (reported as log2) of selected vitamin D–related genes collected by laser capture microdissection from the benign epithelium of fresh frozen radical prostatectomy specimens. Gene expression by ancestry group and correlation to the percent West African ancestry for (A) VDR, (B) CYP2R1, (C) CYP27B1, (D) CYP27A1, (E) CYP24A1, (F) and DHCR7 (European American [EA], n = 13; African American [AA], n = 13). P <0.1; differences between ancestry determined by 2-sided Wilcoxon signed-rank test, and correlations between gene expression and percent ancestry determined by Spearman’s rank coefficient.