Tumor autonomous effects of Vitamin D deficiency promote breast cancer metastasis

Abstract

Patients with breast cancer (BCa) frequently have preexisting Vitamin D deficiency (low serum 25-hydroxyVitamin D) when their cancer develops. A number of epidemiological studies show an inverse association between BCa risk and Vitamin D status in humans, although some studies have failed to find an association. In addition, several studies have reported that BCa patients with Vitamin D deficiency have a more aggressive molecular phenotype and worse prognostic indicators. However, it is unknown whether this association is mechanistically causative and, if so, whether it results from systemic or tumor autonomous effects of Vitamin D signaling. We found that ablation of Vitamin D receptor expression within BCa cells accelerates primary tumor growth and enables the development of metastases, demonstratingatumorautonomouseffectofvitaminDsignalingtosuppressBCametastases. We show that Vitamin D signaling inhibits the expression of the tumor progression gene Id1, and this pathway is abrogated in Vitamin D deficiency in vivo in 2 murine models of BCa. These findings are relevant to humans, because we discovered that the mechanism of VDR regulation of Inhibitor of differentiation 1 (ID1) is conserved in human BCa cells, and there is a negative correlation between serum 25-hydroxyVitamin D levels and the level of ID1 in primary tumors from patients with BCa.