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8/12/2019 The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancer development and how it has been expl
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
Abstract
The epidermal growth factor receptor has long been known to have a role in cellular
proliferation, implementing its signalling in cancer (Cohen, 1965). This has been supported
by genome-wide studies identifying enrichment for mutations in EGFR family members, in a
variety of human tumour genomes (Kandothet al., 2013). Often, a characteristic molecular
defect in tumours is gene amplification of ERBB2, leading to overexpression of the EGFR
family memberERBB2 (Slamonet al., 1989). The elucidation of this proteins role as a
central member of the EGF signalling network(Yarden and Sliwkowski, 2001)and analysis of
its molecular structure, has provided a basis for the discovery of drugs such as lapatinib and
trastuzumab,(Carteret al., 1992;Rusnaket al., 2001)that have had an impact on clinical
outcomes (Baselgaet al., 1996;Geyeret al., 2006). This essay looks into some of the
experiments and studies that have been instrumental in recognition of ERBB2 as an
essential modulator of mitogenic signalling, design of drugs to target the protein and the
clinical applications of these agents.
Word Count: 150
Target identification
The epidermal growth factor receptor (EGFR)-like protein family member, HER2 (now knownas ERBB2), was first cloned through a screen of a human genomic DNA library using a
restriction digest product of a vector containing the genome of avian ethroblastosis virus
(AEV) as a hybridisation probe, which chosen as it included the known viral oncogene v-
erbB(Coussenset al., 1985). This encodes a protein with high sequence similarity to EGFR,
differing through a series of deletions (Downwardet al., 1984). The resultant isolated
fragment was sequenced and used to design a probe for a human cDNA library, the longest
isolated clone that strongly bound to this probe and weakly bound an EGFR probe, was
then sequenced, to obtain the coding sequence of ERBB2(Coussenset al., 1985).Using a
combination of in situ hybridisation of 3H-labelled probes to human chromosomes and
detection of the gene on southern blots of rat-human hybrid cell DNA preparations with
differential human chromosomes complement, the gene was mapped to chromosome
17q21, the coincident position toneu, a growth factor-like gene previously discovered to be
activated in rat neuroblastoma cells (Schechteret al., 1984;Coussenset al., 1985)Protein
sequence analysis later showed that ERBB2is the human homologues of neu(Yamamoto
et al., 1986).
Independently produced clones were used to probe southern blots of DNA from several
primary human tumours, finding a 30-fold amplification of the gene in salivary
adenocarcinoma (Sembaet al., 1985). This was confirmed in vivobyhybridisation of ERBB2
probes to a large sample of solid tumour genomes (Yokotaet al., 1986). Further studies
found evidence for amplification in other malignant cells, such as gastric cancer cell lines
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
(Fukushigeet al., 1986)and mammary cancer primary tumours (Kinget al., 1985). ERBB2
amplification was also found to be present in 20-30% of breast cancers and the extent of
amplification is a prognostic indicator for the disease (see fig.1) (Slamonet al.,
1987).Crucially, ERBB2 gene amplification also correlates with increased expression of
ERBB2(Slamon et al., 1987; Slamon et al., 1989).This is associated with increasedneoplastic transformation efficiency of the rat NIH/3T3 cell line, as those transfected with
ERBB2under the control of a high activity viral promoter, produced a comparable
transformation efficiency to potent oncogenes such as v-H-ras (Di Fioreet al., 1987). The
result of implanting transformed NIH/3T3 cells into nude mice also supports ERBB2s
overexpression as a factor in promoting metastases (Yu and Hung, 1991). However there is
controversy whether this effect requires additional factors to be present, as a study observed
that co-overexpression of another possible oncogene14-3-3, with ERBB2 conferred a
higher risk of breast cancers obtaining metastatic properties, such as adhesion
dysregulation(Luet al., 2009).
Target verification
Kinase assay, through visualisation of the phoso-ERBB2 on polyacrylamide gel separations
of purified ERBB2 extracts treated with 32P labelled ATP and acid hydrolysis followed by
polyacrylamide gel electrophoresis (PAGE) comparison with phospho-amino acid residues,
established ERBB2 as a protein tyrosine kinase (PTK) (Akiyamaet al., 1986). Also, the
epidermal growth factor (EGF) signalling network has been found to include many
downstream effectors involved in cellular survival and proliferation (see fig. 2), including
MAP-K (Riese and Stern, 1998)and PI3K (Okanoet al., 2000). An experiment looking into
this pathway demonstrated interaction between the EGF signalling and Ras through
transactivation by G-protein coupled receptors, by showing stimulation with the G-protein
receptor ligands leads to Shc association with EGFR and ERBB2, initiating formation of a
mitogenic signalling complex on the cell membrane (Luttrellet al., 1997)(Daubet al., 1996;
Luttrellet al., 1997). A recent study that has suggested cross-talk between EGFand MAP-K
signalling in a cancerous state, using fluorescent immunolocalisation to visualise co-
localisation of ERBB2 with EphrinB1, a possible modulator of Erk1/2, in breast cancer cell
lines when a known prognostic marker, PTPN13 depletion, is also present, also , a known
oncogenic mutation increases this interaction (Vermeeret al., 2012).
Interestingly, ERBB2 is subject to transactivation by autophosphorylation, through
dimerization with EGFR on stimulation with EGF, with in vitrokinase assay of protein
extracts treated with the cross-linking agent EDAC, showing a 360kDa band on an SDS-
PAGE western blot, which could be seen on staining with ERBB2 and EGFR antibody and
was only present when the preparation was incubated with EGF (Goldmanet al., 1990).
This, combined with the lack of characterized ligand, led to the model that ERBB2 acts
exclusively as a co-receptor for dimerization with other EGFR family members. A hierarchy
of ERBB2 dimer interactions was also discovered using kinase assays of cell lines
transformed with internally expressed ERBB2 antibody, determining that EGFR family
members activation is enhanced by ERBB2 differentially, depending on stimulus and
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
strikingly downstream effectors of the pathway, such as MAP-K, showed differential tyrosine
phosphorylation selectively on ERBB2 downregulation with certain specific stimuli only
(Graus-Portaet al., 1997). Further evidence was gathered by selective blocking of ERBB2
function by a specific tyrosine kinase inhibitor and assay of the effect on ERBB3
phosphorylation in primary breast cancer tumour cell lines. The inhibition caused not onlyreduced phosphorylation of ERBB3, a protein shown to have reduced autophosphorylation
potential, but also cell cycle arrest of the cells (Holbroet al., 2003). The crystal structure of
ERBB2 (see fig. 3) has confirmed its role as a ligand free receptor (Burgesset al., 2003).
This evidence places ERBB2as the central binding partner for other EGFR family members
(see fig.3) and a key target for cancer therapy.
Drug discovery
Efforts in targeting ERBB2 sought to deactivate the protein through binding to specific
antibodies, to counteract its overexpression in many cancers. Work using murine antibody in
breast tumour cell lines yielded striking anti-proliferative results with cells showing new
sensitivity to TNF- and reduced cell number compared to the same line treated with
different antibody (Hudziaket al., 1989). This soon led to humanisation of the antibody by
replacement of the mouse constant domain with human in clones derived from PCR
amplification of the hybridomas from which antibody was derived and alteration of the
sequence based on a molecular model of human heavy and light chain structure, the
resulting variants were then produced in human kidney cells through transfection and tested
for their ability to inhibit cell proliferation, a variant was successful and this led to the
antibody, known as trastuzumab, to enter clinical trials (Carteret al., 1992; Baselgaet al.,
1996).
Another strategy involved the production of tyrosine kinase inhibitors (TKIs) specific to the
EGFR family. One inhibitor, lapatinib, has been designed with a dual specificity for both
ERBB2 and EGFR based on the reported overexpression of both proteins in many cancers.
Screening of large small molecule libraries for inhibitory activity measured by reduction of
malignancy in various cell lines overexpressing the proteins yielded an initial candidate
(Cockerillet al., 2001). A model for the binding of the isolated molecule was produced to
predict modifications that improved affinity based on a crystal structure of a binding pocket
for a chemically similar protein kinase and these were applied before testing efficacy bykinase and cell proliferation assays (Shewchuket al., 1999;Cockerillet al., 2001;Rusnaket
al., 2001).
More recent evidence supports the use of a combination of these drugs to prevent primary
resistance to therapy that sometimes can occur, as they have molecularly distinct targets
(Xiaet al., 2005). This was also supported by assay of downstream targets in the EGF
network, showing decreased phospho-Erk and phosphor- Akt in cells treated with the drugs
in combination (Wainberget al., 2010).
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
Clinical applications
Trastuzumab was approved for treatment of metastatic ERBB2 overexpressing breast
cancer either alone, or in combination with cytotoxic therapy, by the federal drugsadministration in 1998 (Yarden and Pines, 2012). It was shown to be particularly useful as
an adjuvant, increasing median survival by over 4 months in combination with various forms
of chemotherapy .It was also found to be useful in other clinical settings such as following
primary breast cancer removal surgery (Romondet al., 2005). However, continued treatment
was shown not to improve poor outcomes in patients with advanced breast cancer
progressing in spite of trastuzamab treatment (Montemurroet al., 2006). Lapatinib, however,
has had a large effect on survival as an adjuvant to chemotherapy in patients with metastatic
breast cancer that had progressed beyond trastuzamab treatment, e (Geyeret al., 2006). Its
use has also been explored in many other cancers such as ERBB2 overexpression CNS
tumours, where trastuzamab treatment has failed (Linet al., 2008). However the drugsimpact in monotherapy has shown to be limited (Bursteinet al., 2008).
Models looking at reasons for the decreased associated mortality with breast cancer since
1990 have identified this adjuvant therapy as a significant factor in improved patient
outcomes(Berryet al., 2006). And despite mechanisms for resistance emerging in both
treatments (Rosset al., 2009)promising clinical trials from combination therapy strategies
discussed earlier provide promise for cancer treatment by ERBB2 downregulation for the
future (Blackwellet al., 2010).
Word count: 1350
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Open book essay, The role of overexpression of theERBB2 (HER2/NEU) oncogene in cancer development and how it has been exploited to improve cancer treatment, 07/01/2014.
Appendix
Figure 1. KaplanMeier curves of sampled breast cancer patients with amplified and axillary lymph gland involvement in the disease over
84 months. Comparison of disease free (relapse) survival probability in patients with (A) ERBB2 amplification and those without
amplification (C) Patients with a quantified amplification of ERBB2 of >5 an d those with no amplification. Also comparison of overall
survival probability in patients with (B) ERBB2 amplification and those without amplification and (D) those with quantified amplification of
ERBB2 of >5 and those with no amplification. Prognosis is affected in both patient groups but most significantly by possession of >5
copies of ERBB2 (Slamon et al., 1987).
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Open book essay, The role of overexpression of theERBB2 (HER2/NEU) oncogene in cancer development and how it has been exploited to improve cancer treatment, 07/01/2014.
Figure 2. The EGF signalling network. Numbers in the input layer (a) represent the ERB family (1 corresponding to EGFR, 2, ERBB2 3,
ERBB3 etc.) high affinity binding targets for EGF and NRG4 ligands are also shown. The signal processing layer (b) includes pathways
implicated in cellular proliferation such as MAP-K, stimulated by the ERBB2 and ERBB3 heterodimer and EGFR homodimer, and PI13K-Akt
signalling pathways, stimulated solely by ERBB2 and ERBB3 homodimer (Yarden and Sliwkowski, 2001)
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Open book essay, The role of overexpression of theERBB2 (HER2/NEU) oncogene in cancer development and how it has been exploited to improve cancer treatment, 07/01/2014.
Figure 3. The crystal structure of the extracellular domains of A) ERBB2 and B) EGFR. The similarity in the domain structure of ERBB2 to
ligand bound active and the bridging of the 2 ligand binding domains mimicking the interaction of EGF with EGFR, both supports the
theory that ERBB2 is in fact constitutively active and explaining its lack of ligand. This ligand independent activation also supports the
theory putting ERBB2 as the key heterodimer activation partner for the EGF signalling network (Burgess et al., 2003).
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
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8/12/2019 The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancer development and how it has been expl
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Christian Belton, Student No: 110026567, BGM3024, The Molecular Basis of Cancer, Openbook essay, The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancerdevelopment and how it has been exploited to improve cancer treatment, 07/01/2014.
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