Mucin 1 enhances the tumor angiogenic response by activation of the AKT signaling pathway

Abstract

Although the hyper-glycosylated transmembrane protein Mucin 1 (MUC1) is aberrantly overexpressed in human breast carcinoma, the biological significance of MUC1 overexpression is unclear. This study showed that MUC1 expression promoted the synthesis and secretion of vascular endothelial growth factor (VEGF) through the AKT signaling pathway. Increase VEGF production through MUC1 expression had a number of effect. First, MUC1 transfection increased expression of VEGF in breast cancer cells. Second, MUC1-mediated VEGF induction was attenuated by a chemical inhibitor of AKT or MUC1 knock-down by MUC1 siRNA. Third, MUC1 expression led to the activation of insulin-like growth factor-1 receptor, which correlated with VEGF expression. In addition, when MDA-MB-231 human breast cancer cells were directly injected into NOD/SCID mice, MUC1 expression accelerated xenograft tumor growth in vivo. Finally, MUC1 expression enhanced tumor growth and angiogenesis in a PyMT-MMTV/hMUC1 transgenic mouse model. Concurrent with these results, analysis of a human tissue microarray identified a high correlation between MUC1 and VEGF expression in human breast carcinoma. The current report is the first to demonstrate that MUC1 expression promotes angiogenesis in human breast cancer in vivo and in vitro. Oncogene (2012) 31, 2187-2198; doi:10.1038/onc.2011.410; published online 19 September 2011