• What is ERBB2?
  • ERBB2 in Breast Cancer
  • Clinical Trials


HER2 belongs to a family of receptor tyrosine kinases (RTKs) that includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The gene for HER2 is located on chromosome 17 and has been found to be amplified with an increased copy number in several cancers (Jorgensen 2010). Amplification of HER2 has been found to promote tumorigenesis and to be involved in the pathogenesis of several human cancers (Moasser 2007).

To date, no ligand has been identified for HER2. However, HER2 appears to be the preferential dimerization partner for all members of the ERBB family (Graus-Porta et al. 1997). The binding of ligand followed by HER2 hetero-dimerization results in activation of HER2 tyrosine kinase activity. Activated HER2 then phosphorylates its substrates, leading to activation of multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).


Figure 1.
Schematic of HER2 signaling pathway. Growth factor binding results HER2 heterodimerization and activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Chanjuan Shi, M.D., Ph.D., Graham T. Watson, M.D., Leora Horn, M.D., M.Sc., Paula Pohlmann, M.D., Ph.D., Laura W. Goff, M.D.

Suggested Citation: Lovly, C., C. Shi, G. Watson, L. Horn, P. Pohlmann, L. Goff. 2015. HER2 (ERBB2). My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/erbb2/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

HER2 (ERBB2) in Breast Cancer

Human epidermal receptor growth factor 2 (HER2, ERBB2) overexpression occurs in 18–20% of breast cancer (Owens et al. 2004; Slamon et al. 1987; Yaziji et al. 2004). HER2 overexpression arises from multiple mechanisms; gene amplification is the most common. Overexpression in general is measured by IHC and gene amplification is measured by FISH methods. Activating mutations in HER2 are estimated to occur at a frequency of 1.6–2.0% in breast cancer (Bose et al. 2013; COSMIC).

HER2 overexpression in breast cancer carries prognostic and predictive significance. In the adjuvant setting, HER2 status is prognostic for outcomes and predictive for outcomes with HER2-targeting therapies such as trastuzumab- based therapy and with anthracycline-based therapies (NCCN 2012). In the metastatic setting, HER2 status predicts outcomes with trastuzumab and HER2-targeting agents (NCCN 2012).

Recently, in patients without HER2 gene amplification, activating HER2 mutations have also been identified (Bose et al. 2013). Preclinical studies have indicated that some HER2 mutations may result in sensitivity or resistance to trastuzumab, neratinib, or lapatinib, depending on the specific mutation (Bose et al. 2013).

Gene or Protein Invasive Breast Cancer Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer HER2 positive Invasive Breast Cancer Triple-negative Invasive Breast Cancer
HER2 amplification 18% (Slamon et al. 1987) 18% (Slamon et al. 1987) 100% N/A
HER2 overexpression 18–20% (Owens et al. 2004Yaziji et al. 2004) 8% (Blows et al. 2011) 100% N/A
HER2 mutations 1.6–2.0% (25 cases reported in Bose et al. 2013; COSMIC) 8 cases reported (Bose et al. 2013) One case reported (Bose et al. 2013) No cases reported (Bose et al. 2013)
NOTE: ER = estrogen receptor; PR = progesterone receptor; N/A = not applicable

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2013. HER2 (ERBB2) in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/erbb2/ (Updated April 10).

Last Updated: April 10, 2013

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