HER family signaling is deregulated in a number of subtypes of human cancers. This has been most commonly recognized and etiologically established in breast cancers, lung cancers, and glioblastomas (refer to ). Many other cancers have increased expression of HER family members, however their role in other cancers is less well established.
Genomic level abnormalities in HER genes reported in human cancers
Overexpression of HER2 due to gene amplification is found in 25–30% breast cancer and confers a particularly aggressive biology 11
. HER2 overexpression is also uncommonly seen in cancers of the esophagus, stomach, ovaries, and endometrium. Mutations in HER2 are rarely found in these cancers and overexpression appears to be the principal mechanism by which HER2 mediates tumorigenesis in these cancers. Numerous experimental models have confirmed that HER2 is potently transforming when overexpressed and several mouse transgenic models have confirmed the role of its rodent homologue Neu
in mammary tumorigenesis 12
. Tumors arising in Neu
transgenic mice have increased expression of the mouse HER3 homologue, activation of src and activation of the PI3K/Akt signaling pathway (recently reviewed in 13
). Importantly, tumors arising in Neu
transgenic mice are highly dependent on continued overexpression of Neu
and in models wherein transgenic expression can be turned off, the disease completely regresses including both the primary mammary tumors and their lung metastases 14
. HER2 kinase domain mutations are seen in a small subset of lung cancers, particularly in asian populations 15
. These HER2 mutations are associated with increased kinase activity and transformation in vitro 16
. Transgenic models of these HER2 mutations have not yet been reported.
EGFR is frequently amplified and overexpressed in nearly half of all glioblastomas. In these cancers, amplification is frequently associated with deletion mutations involving the ECD of EGFR of which one particular variant, called EGFRvIII is the most common 17
. These mutations result in the constitutive activation of EGFR and are frequently associated with additional mutations in the cell cycle regulatory gene INK4a-ARF. Mouse transgenic models confirm that mutant EGFR is tumorigenic, but requires additional mutations in cell cycle arrest pathways 18
EGFR is altered through point mutation or deletion mutation in the kinase domain in 10–15% of NSCLCs in the U.S. and in 30–50% of NSCLCs in Asia. The mutations are clustered within four exons encoding the kinase domain 19–22
. These mutations produce a spectrum of biochemical effects from increased kinase activity to ligand-independent constitutive activity 21, 23, 24
. Destabilization of the autoinhibited conformation of the EGFR ICD has been proposed to explain constitutive activation of these EGFR mutants 23
. Based on the solved EGFR ICD structure, the L858R mutation in the A-loop and the deletion Del(746–750) in the α-C helix are predicted to disrupt the autoinhibited ICD. EGFR is overexpressed without mutation in a much larger subset of NSCLCs, however its etiologic role in these scenarios is not well established. The etiologic role of at least some of the common EGFR mutant alleles in tumorigenesis has been confirmed by in vitro
and in vivo
experiments. These EGFR mutants are transforming in fibroblast and epithelial cell models, and cause lung tumors when expressed in mice lung epithelia 25–28
. EGFR is also widely overexpressed in many other epithelial cancers including cancers of the head and neck, ovary, cervix, bladder, esophagus, stomach, endometrium, colon and breast.
HER3 is not currently characterized as a proto-oncogene and significant genomic level alterations in HER3 have not been found in tumors 29
. However this does not undermine its role and its activation in cancers driven by EGFR or HER2. A significant body of data suggest that HER2 and HER3 are partners in signaling and in transformation. The HER2-HER3 heterodimer is the most active signaling dimer within the HER family 8
. Tumors that arise in mice due to oncogenic ErbB2 have increased expression of ErbB3 and similarly, tumors from patients with HER2 amplified breast cancer have increased expression of HER3 30
. HER3 is an obligate partner for HER2 in transformation and HER2 is unable to transform cells in the absence of HER3 31
. HER3 is likely also involved in EGFR-driven tumors, although this relationship is not as well characterized. The mutational activation of EGFR in lung cancers is associated with the phosphorylation of HER3 and coupling of HER3 to PI3K 32
HER4 is the least well characterized member of the HER family. But existing evidence does not implicate HER4 overactivity in tumorigenesis, and in fact HER4 signaling has been associated with differentiation, cell death, or reduced tumorigenicity 33, 34
. Very rare mutations of the HER4 kinase domain have been reported in one study, but at this time the biological significance of this finding is not clear 35
Although many questions still remain (Text box 1
) the evidence to date clearly implicates HER proteins in the pathogenesis of certain subtypes of human cancer.
Text Box 1. Outstanding questions in HER biology
- How does dimerization induce activation of the kinase domain?
- Do ligands play a role in the progression of cancers with HER mutation or amplification?
- Are cancers without HER mutation or alteration dependent on HER signaling?
- Does HER4 have a role in tumorigenesis?
- Why are EGFR mutations in lung cancer so much more common in Asia?
Effectors of oncogenic HER signaling
The frequent activation of HER proteins in many types of human cancer attest to their critical role in regulating pathways important for tumorigenesis and tumorigenic survival. These pathways include the Ras-MAPK pathway, the PI3K/Akt pathway, the JAK/Stat signaling pathway, and PLCγ. The significance of these pathways in tumorigenesis is underscored by the fact that the activation of each of them is frequently found in many types of cancers. However there are both similarities and differences in the abilities of EGFR or HER2 to influence these pathways. Activated EGFR and HER2 can both increase Ras-MAPK signaling making additional mutations in this downstream pathway redundant. Consistent with this notion, Ras and B-Raf mutations although common across all cancers, are rare in EGFR-mutated lung cancers, in HER2 overexpressing breast cancers, or in EGFR amplified glioblastomas 36–38
. STAT3 is activated by EGFR and HER2 and is activated in EGFR mutated lung cancers and glioblastomas 39–42
The PI3K/Akt pathway appears to be a pivotal pathway for tumorigenesis and is widely activated in many tumors including tumors driven by activated EGFR or HER2. EGFR and HER2 do not have direct binding sites for PI3K. However HER3 has seven PI3K-binding sites and when phosphorylated by EGFR or HER2, is a potent activator of PI3K 43
. EGFR can also activate PI3K through the docking protein Gab1 44
. HER2 amplified breast cancers have increased expression and phosphorylation of HER3 and increased activity of downstream PI3K/Akt signaling 30
. Akt can also be activated through the loss of PTEN in many cancers, however loss of PTEN is rarely seen in HER2 amplified breast cancers, consistent with its presumed redundancy when HER2-HER3 signaling is activated 45
. Activating mutations of PI3K are however seen in HER2 amplified breast cancers. Since HER2 is capable of activating PI3K signaling through its partner HER3, it is currently difficult to hypothesize the advantage confered by PI3K mutation in HER2 amplified tumors. It is possible that some of the functions of mutant PI3K are not redundant with the upstream activation of wildtype PI3K by HER3. For example, mutationaly activated PI3K is active within the cytoplasmic compartment, whereas HER2-HER3 activated PI3K is active primarily at the plasma membrane.
EGFR-mutant lung cancers also have activation of HER3 and downstream PI3K/Akt pathway, and these are not known to be associated with mutations in PI3K or PTEN 32, 46
. However EGFR amplified glioblastomas have frequent activation of Akt and in these cancers this is often due to the loss of PTEN. It is currently difficult to understand the advantage conferred by the loss of PTEN in EGFR amplified glioblastomas, since it would seem to be redundant if activated EGFR can signal the activation of HER3 and PI3K/Akt signalling. However there is a lot more that is to be learned about EGFR signaling in glioblastomas and compared with EGFR signaling in lung cancers. It is possible that the EGFR oncogenes with ECD mutations commonly seen in glioblastomas are not intrinsically efficient at activating HER3, necessitating PTEN deletion to activate Akt signaling. On the other hand, the EGFR kinase domain mutations in lung cancer increase the ability of EGFR to activate the PI3K/Akt pathway, and both HER3 and Gab1 have bene implicated in this circuity 32, 46
. Clearly much more work in this area is needed to better understand the differences between activated EGFR in lung cancers and in glioblastomas.