ECM1 Regulates Cell Proliferation and Trastuzumab Resistance Through Enhancement of EGF-Signaling

摘要

The Extracellular Matrix Protein 1 (ECM1) is a secreted glycoprotein and plays an important role in angiogenesis in blood vessel endothelium. Recently, it was reported that ECM1 induces tumorigenesis through promoting development of blood vessel. Moreover, ECM1 is highly expressed in various types of cancer patients and predicted as a marker for tumor development. Here, I established trastuzumab, a HER2 target therapeutical antibody, resistant breast cancer cell lines and analyzed protein expression profiles with two dimensional digest-LC-MS/MS. Increased level of ECM1 was detected in trastuzumab resistant (TR) cells and this increased level of ECM1 was shown to be responsible for cell proliferation and trastuzumab resistance. ECM1-induced Galectin-3 cleavage through activation of MMP-9 not only regulated MUC1 expression but also increased EGFR and HER3 protein stability. This stabilization of receptor tyrosine kinases led to ERK activation and increased cell proliferation. Interestingly, ECM1 was shown to enhance the phosphorylation of EGFR and ERK upon EGF treatment through physical association with EGFR. These data provide the evidence that ECM1 has an important role in both cancer development and trastuzumab resistance in breast cancer. I also provide evidence that targeting ECM1 with antibody against ECM1 could be new therapeutic approaches for breast cancer patients.