ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

Abstract

Overexpression of ErbB2 is found in several types of human carcinomas. In breast tumors, ErbB2 overexpression is detected in up to 20% of patients. Breast cancers in with ampliication of ErbB2 are characterized by rapid tumor growth, lower survival rate and increased disease progression. The molecular mechanisms underlying the oncogenic action of ErbB2 involve a complex signaling network that tightly regulates malignant cell migration and invasion and hence metastatic potential. Recent eforts have been made to identify gene expression signatures of ErbB2-positive invasive breast cancers that may represent important mediators of ErbB2-induced tumorigenesis and metastatic progression.In this chapter, we will discuss the canonical ErbB2 signaling pathways responsible for tumor growth and dissemination along with newly identiied mediators such as adaptor protein p130Cas and miRNAs. From a therapeutic point of view, the treatment with anti-ErbB2 monoclonal antibody trastuzumab has greatly improved the outcomes of patients with ErbB2 aggressive cancer. Nevertheless, de novo and acquired resistance to trastuzumab therapy still represent a major clinical problem. In the second part of the chapter, we will provide an overview of the mechanisms so far implicated in the onset of resistance to targeted therapy and of the new strategies to overcome resistance.

Downregulation of ERBB3 decreases the proliferation, migration and invasion of cervical cancer cells though the interaction with MTK‑1

“…ERBB3 may participate in the development of different types of cancer by regulating the migration and invasion of tumor cells ( 12 , 13 ). A recent study has indicated that ERBB3 may promote the development of breast cancer by increasing the migratory and invasive abilities of breast cancer cells ( 9 ), while the increased degradation of ERBB3 mediated by NRDP1 was identified to reduce the migratory and invasive abilities of human glioma cells ( 10 ). In the present study, ERBB3 siRNA silencing was identified to significantly reduce the proliferative, migratory and invasive abilities of cervical cancer cells, indicating that ERBB3 expression is important for the migration and invasion of cervical cancer cells.…”

“…However, the functionality of ERBB3 in the pathogenesis of this disease remains unclear. A previous study indicated that ERBB3 may promote the migration and invasion of breast cancer cells and increased resistance of cancer cells to targeted therapy ( 9 ). In contrast, degradation of ERBB3 mediated by E3 ubiquitin-protein ligase NRDP1 (NRDP1) was demonstrated to inhibit the migration and invasion of human glioma cells ( 10 ).…”

Proteomic Analysis of Erbb2 - A Potential Breast Cancer Marker: An Integrated Bioinformatics Strategy

“…The prediction of individual gene function made easier by using computational analysis that aids in finding cellular interaction networks, and their associated cellular physiological mechanisms. The activation of ERBB2 associated downstream signaling pathways [7,9], will help in understanding the molecular mechanisms leading to breast cancer. Genomic location, function, catalytic activity, Protein structure and domains, interactive functional partner's, and post-translational modifications of the ERBB2 gene have been accumulated by Bioinformatics data analysis.…”

“…Moderate affinity and promiscuity of recognition still a proven challenge for targeting Protein-Protein Interactions (PPIs), despite the enormous research in the discovery of anticancer drugs using ERBB2/p130C. However, resistance to ERBB2-targeted treatments was reported due to the contribution of various factors [7,[9][10].…”

“…Playa significant role in cell growth, production, existence, and motility, any mutation of ERBB2 will cause cancers and the over-expression will cause activation of downstream signaling. The underlying mechanism involved in ERBB2 oncogenic activity is a complex signaling network, as both homo/heterodimers upon ligand binding tightly regulate migration, metastasis, and invasion of the malignant cell [7][8]. Humanized monoclonal antibodies and receptor tyrosine kinase inhibitors are the recently proposed anti-ERBB2 therapies for breast cancer treatmentwhose overexpression alters cell proliferation and survival [9][10].…”