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.

MUC1 and metastatic cancer

“…77 Though MUC1 is a transcriptional target of HIF1-α as discussed above, MUC1 also interacts with HIF1-α in the cytoplasm and promotes transcriptional upregulation of HIF1-α targets such as leptin, TGFβ3 and VEGF. [78][79][80] Furthermore, MUC1 and VEGF expression correlate in human breast cancer cell lines, and MMTV-PyMT mice expressing human MUC1 display more angiogenesis than MMTV-PyMT mice on a Muc1 null background, 81 further supporting a role for MUC1 in the onset of angiogenesis.…”

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

“…The glycosylated extracellular domain of MUC1 inhibits anoikis by shielding death receptors such as the Fas ligand on the cell surface [125]. MUC1 enhances carcinogenesis by activation of the Akt pathway that regulates cell proliferation and migration [149,150]. Activation of the MUC1 cytoplasmic tail leads to the phosphorylation of Akt and Bad, resulting in the upregulation of mitochondrial Bcl-Xl and inhibition of apoptosis [132,151].…”

Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

“…Another protein to mention is MUC1, a hyperglycosylated transmembrane protein expressed on normal secretory epithelial cells, while 90% of carcinomas show aberrant MUC1 expression (12,13). Preclinical models have demonstrated that MUC1 overexpression can stimulate VEGF synthesis and secretion through activation of the AKT signaling pathway (12) and can contribute to hypoxia-driven angiogenesis (13).…”