This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase.
ERBB2 is commonly amplified in primary breast cancer (25%-30% of cases), defining a specific class of tumors frequently treated with compounds trastuzumab, pertuzumab and lapatinib.
ERBB2 also amplified (and overexpressed) in bladder carcinomas, in Barrett carcinoma, ovarian cancer, carcinoma of the salivary glands, endometrial, gastric, and prostate cancers. ERBB2 overexpression (without gene amplification) is observed in tumors of various other types.
Somatic point mutations (mainly substitutions and insertions) are observed in cancers of endometrium, stomach, CNS (glioblastoma), liver, ovary, breast, large intestine, lung and pancreas…These mutations impact the tyrosine kinase activity.
To date, one year of trastuzumab in combination or after chemotherapy is the standard adjuvant therapy for breast cancer patients with ERBB2-overexpressing tumors. However, primary and secondary resistance to trastuzumab is observed both in early and advanced disease. Several mechanisms are described as possible determinants of trastuzumab failure, and several new anti-ERBB2 strategies are in development. Lapatinib, a tyrosine kinase inhibitor active on both ERBB1 (EGFR) and ERBB2 is currently approved in advanced disease after trastuzumab failure. Other molecules such pertuzumab, which binds the ERBB2 dimerization domain, or the pan-ERBB tyrosine kinase inhibitor neratinib are under evaluation.
References (open access):
Trastuzumab-based neoadjuvant therapy in patients with HER2-positive breast cancer. Chang HR. Cancer. 2010 Jun 15;116(12):2856-67.
Management of ErbB2-positive breast cancer: insights from preclinical and clinical studies with lapatinib. Vogel C, Chan A, Gril B, Kim SB, Kurebayashi J, Liu L, Lu YS, Moon H. Jpn J Clin Oncol. 2010 Nov;40(11):999-1013.
AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo. Xie H, Lin L, Tong L, Jiang Y, Zheng M, Chen Z, Jiang X, Zhang X, Ren X, Qu W, Yang Y, Wan H, Chen Y, Zuo J, Jiang H, Geng M, Ding J. PLoS One. 2011;6(7):e21487.
Genome profiling of ERBB2-amplified breast cancers. Sircoulomb F, Bekhouche I, Finetti P, Adélaïde J, Ben Hamida A, Bonansea J, Raynaud S, Innocenti C, Charafe-Jauffret E, Tarpin C, Ben Ayed F, Viens P, Jacquemier J, Bertucci F, Birnbaum D, Chaffanet M. BMC Cancer. 2010 Oct 8;10:539.