Estrogen-Modulated Response of Breast Cancer to Vitamin D and its Analogs: Role of IGF

摘要

Dihydroxyvitamin D3 (VD3) affects essential cell processes such as proliferation, differentiation, and apoptosis in a diverse cell types, including cancer cells. In this study, we investigate whether VD3 could inhibit proliferation of breast cancer cells (BCCs) by suppressing the expression and signaling of endothelial differentiation gene-encoded G protein-coupled receptors (EDG Rs). EDG Rs transduce major effects of lysophospholipid growth factors (LGFs), such as lysophosphatidic acid (LPA) and sphingosine-1 phosphate (S1P), on estrogen receptor-negative and estrogen receptor-positive BCCs, including stimulation of proliferation and growth-independent functions. MDA-MB- 453 and MCF-7 BCCs used in this study express predominantly Edg-3 > 4 > 5 and - 2, but not Edg-1. We have shown that VD3, at 10(exp -10) to 10(exp -8) M, suppressed significantly mRNA levels of Edg-2, -3,-5, but not Edg-4 in both lines of BCCs as quantified by TaqMan real-time PCR. VD3 also inhibited proliferative responses of LGF-stimulated BCCs and modulated LPA- and S1P- induced SRE reporter responses of BCCs. These data identify a novel mechanism of VD3 action on the abnormal growth of BCCs and suggest that EDG Rs are potential targets for specific therapy of some human breast cancers.