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.
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.
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.
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
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).
NOTE: ER = estrogen receptor
; PR =
; N/A = not applicable
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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