Data from The Relative Expression of ERα Isoforms ERα66 and ERα36 Controls the Cellular Response to 24R,25-Dihydroxyvitamin D3 in Breast Cancer

Abstract

<div>Abstract<p>Vitamin D3 and its metabolites have antitumorigenic properties <i>in vitro</i> and <i>in vivo</i>; however, clinical trials and retrospective studies on the effectiveness of vitamin D3 oral supplementation against cancer have been inconclusive. One reason for this 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)<sub>2</sub>D<sub>3</sub>, a vitamin D<sub>3</sub> metabolite that is active in chondrocyte proliferation and differentiation, has antitumorigenic properties in estrogen receptor alpha-66 (ERα66)–positive (ER<sup>+</sup>) breast cancer, but not in ERα66-negative (ER<sup>−</sup>) breast cancer. Here we show that 24R,25(OH)<sub>2</sub>D<sub>3</sub> is protumorigenic in an <i>in vivo</i> mouse model (NOD.<i>Cg-Prkdc<sup>scid</sup>Il2rg<sup>tm1Wjl</sup></i>/SzJ (NSG) mice) of ER<sup>−</sup> breast cancer, causing greater tumor growth than in mice treated with vehicle alone. <i>In vitro</i> results indicate that the effect of 24R,25(OH)<sub>2</sub>D<sub>3</sub> is via a membrane-associated mechanism involving ERs and phospholipase D. 24R,25(OH)<sub>2</sub>D<sub>3</sub> 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 proapoptotic response of ERα66<sup>−</sup> cells to 24R,25(OH)<sub>2</sub>D<sub>3</sub>, possibly by upregulating ERα66. Silencing ESR1 in ERα66<sup>+</sup> cells increased apoptosis. This suggests 24R,25(OH)<sub>2</sub>D<sub>3</sub> is differentially tumorigenic in cancers with different ERα isoform profiles. Antiapoptotic actions of 24R,25(OH)<sub>2</sub>D<sub>3</sub> require ERα36 and proapoptotic actions require ERα66.</p>Implications:<p>These results suggest that 24R,25(OH)<sub>2</sub>D<sub>3</sub>, which is a major circulating metabolite of vitamin D, is functionally active in breast cancer and that the regulatory properties of 24R,25(OH)<sub>2</sub>D<sub>3</sub> are dependent upon the relative expression of ERα66 and ERα36.</p></div>