Abstract
Vitamin D3 and its metabolites have anti-tumorigenic properties in vitro and in vivo; however, clinical trials and retrospective studies on the effectiveness of vitamin D3 oral supplementation against cancer have been inconclusive. One reason may be that clinical trials ignore the complex vitamin D metabolome and the many active vitamin D3 metabolites present in the body. Recent work by our lab showed that 24R,25(OH)2D3, a vitamin D3 metabolite that is active in chondrocyte proliferation and differentiation, has anti-tumorigenic properties in estrogen receptor alpha-66 (ERα66) positive (ER+) breast cancer, but not in ERα66 negative (ER-) breast cancer. Here we show that 24R,25(OH)2D3 is pro-tumorigenic in an in vivo mouse model (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice) of ER- breast cancer, causing greater tumor growth than in mice treated with vehicle alone. In vitro results indicate that the effect of 24R,25(OH)2D3 is via a membrane-associated mechanism involving ERs and phospholipase D. 24R,25(OH)2D3 increased proliferation and reduced apoptosis in ERα66-negative HCC38 breast cancer cells, and stimulated expression of metastatic markers. Overexpressing ESRI, which encodes ERα66, ERα46 and ERα36, reduced the pro-apoptotic response of ERα66- cells to 24R,25(OH)2D3, possibly by upregulating ERα66. Silencing ESR1 in ERα66+ cells increased apoptosis. This suggests 24R,25(OH)2D3 is differentially tumorigenic in cancers with different ERα isoform profiles. Anti-apoptotic actions of 24R,25(OH)2D3 require ERα36 and pro-apoptotic actions require ERα66. Implications: These results suggest that 24R,25(OH)2D3, a major circulating metabolite of vitamin D, is functionally active in breast cancer. The regulation of 24R,25(OH)2D3 is dependent upon the relative expression of ERα66 and ERα36.
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