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Milk fat globule-EGF factor 8 (MFG-E8) is a key factor that promotes clearance of dying cells by linking apoptotic cells to phagocytes. Early studies of MFG-E8 demonstrated increased serum levels in breast cancer patients, which was therefore designated as breast carcinoma-associated antigen BA64. We recently identified MFG-E8 as a down-regulated gene in murine model mammary tumors caused by erbB2 and cyclin D1 using array analysis of laser capture microdissected (LCM) tissues. These new data better fit an emerging view of MFG-E8 as a potent promoter of apoptotic clearance. To further evaluate the role of MFG-E8 in breast cancer, we used quantitative real-time polymerase chain reaction (qrt-PCR) of LCM extracted RNA from pre-invasive and invasive breast lesions to avoid infiltrating phagocytic cells that express MFG-E8. Here we report that cell-intrinsic MFG-E8 expression is reduced both in mouse erbB2 and cyclin D1 transgenic tumors when compared to normal or preinvasive mammary controls, and in tissues from invasive lesions in patients matched with their own pre-invasive control tissue (n=45) (p<0.001). MFG-E8 siRNA knock-down increased breast cancer cell line survival and promoted proliferation. Our data suggest that MFG-E8 is actually reduced in the actually malignant cells in human breast cancer and this reduction contributes to tumorigenesis by increasing cell survival.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA