Extracellular matrix protein 1 regulates cell proliferation and trastuzumab resistance through activation of epidermal growth factor signaling

Abstract

IntroductionExtracellular matrix protein 1 (ECM1) is a secreted glycoprotein with putative functions in cell proliferation, angiogenesis and differentiation. Expression of ECM1 in several types of carcinoma suggests that it may promote tumor development. In this study, we investigated the role of ECM1 in oncogenic cell signaling in breast cancer, and potential mechanisms for its effects.MethodsIn order to find out the functional role of ECM1, we used the recombinant human ECM1 and viral transduction systems which stably regulated the expression level of ECM1. We examined the effect of ECM1 on cell proliferation and cell signaling in vitro and in vivo. Moreover, tissues and sera of patients with breast cancer were used to confirm the effect of ECM1.ResultsECM1 protein was increased in trastuzumab-resistant (TR) cells, in association with trastuzumab resistance and cell proliferation. Through physical interaction with epidermal growth factor receptor (EGFR), ECM1 potentiated the phosphorylation of EGFR and extracellular signal-regulated kinase upon EGF treatment. Moreover, ECM1-induced galectin-3 cleavage through upregulation of matrix metalloproteinase 9 not only improved mucin 1 expression, but also increased EGFR and human epidermal growth factor receptor 3 protein stability as a secondary signaling.ConclusionsECM1 has important roles in both cancer development and trastuzumab resistance in breast cancer through activation of EGFR signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0479-6) contains supplementary material, which is available to authorized users.

Extracellular matrix 1 (ECM1) regulates the actin cytoskeletal architecture of aggressive breast cancer cells in part via S100A4 and Rho-family GTPases

“…However, studies investigating the mechanisms underlying this phenomenon are rather limited. Two recent reports have supported the hypothesis that ECM1 is involved in the regulation of breast tumor metastasis [13, 14]. Although Lee et al (15) described reduction in S100A4 RNA levels, to the best of our knowledge, this is the first study exploring alterations in cell morphology, the actin cytoskeleton and subsequent effects on S100A4 protein expression and Rho GTPases as potential mechanisms by which ECM1 expression can affect prognosis in breast cancers.…”

“…[4, 7, 5]. Additional evidence indicates that ECM1 overexpression increases lymphatic and microvessel density [8] as well as cellular proliferation and drug resistance to trastuzumab via activation of epidermal growth-factor signaling[13]. Furthermore, ECM1 overexpression is associated with maintenance of the cancer stem cell (CSC) phenotype and with the progression of the epithelial to mesenchymal (EMT) transition [14].…”

Study on the Correlation between Extracellular Matrix Protein-1 and the Growth, Metastasis and Angiogenesis of Laryngeal Carcinoma

“…It was found that ECM1 was highly expressed in a variety of tumors like breast cancer and hepatocellular carcinoma, and was closely related to tumor invasion and metastasis. Additionally, the positive rate of ECM1 expression in metastatic tumors was higher than that in non-metastatic tumors (Lee et al, 2014;Lal et al, 2009;Hou et al, 2004). In-vitro studies revealed that ECM1 could decrease the activity of matrix metalloproteinase-9 (MMP-9) through mutual action with MMP-9 (Fujimoto et al, 2006).…”

Gene Expression Profiles Identified Novel Urine Biomarkers for Diagnosis and Prognosis of High-Grade Bladder Urothelial Carcinoma

“…Wang' s study indicated that ECM1 might enhance cell proliferation and invasiveness by regulating the expression of glucose transporter 1, lactate dehydrogenase and hypoxia-inducible factor 1α (25). There is also evidence that ECM1 potentiates the phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase through physical interaction with EGFR and activation of EGFR signaling in breast cancer development (26). Besides, studies based on pancreatic ductal adenocarcinoma suggested that increased ECM1 expression abrogated the antitumor effect exerted by miR-23a-5p (27).…”