The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancer development and how it has been exploited to improve cancer treatment

8/12/2019 The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancer development and how it has been expl

1/12

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


2/12


(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


3/12


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).


4/12


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


5/12

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).


6/12


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)


7/12


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).


8/12


References

Akiyama, T., Sudo, C., Ogawara, H., Toyoshima, K. and Yamamoto, T. (1986) 'The productof the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity',Science, 232(4758), pp. 1644-6.

Baselga, J., Tripathy, D., Mendelsohn, J., Baughman, S., Benz, C. C., Dantis, L., Sklarin, N.T., Seidman, A. D., Hudis, C. A., Moore, J., Rosen, P. P., Twaddell, T., Henderson, I. C. andNorton, L. (1996) 'Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastaticbreast cancer', J Clin Oncol, 14(3), pp. 737-44.

Berry, D. A., Inoue, L., Shen, Y., Venier, J., Cohen, D., Bondy, M., Theriault, R. and Munsell,M. F. (2006) 'Modeling the impact of treatment and screening on U.S. breast cancermortality: a Bayesian approach', J Natl Cancer Inst Monogr, (36), pp. 30-6.

Blackwell, K. L., Burstein, H. J., Storniolo, A. M., Rugo, H., Sledge, G., Koehler, M., Ellis, C.,Casey, M., Vukelja, S., Bischoff, J., Baselga, J. and O'Shaughnessy, J. (2010) 'Randomizedstudy of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive,trastuzumab-refractory metastatic breast cancer', J Clin Oncol, 28(7), pp. 1124-30.

Burgess, A. W., Cho, H. S., Eigenbrot, C., Ferguson, K. M., Garrett, T. P., Leahy, D. J.,

Lemmon, M. A., Sliwkowski, M. X., Ward, C. W. and Yokoyama, S. (2003) 'An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors', Mol Cell, 12(3), pp.541-52.

Burstein, H. J., Storniolo, A. M., Franco, S., Forster, J., Stein, S., Rubin, S., Salazar, V. M.and Blackwell, K. L. (2008) 'A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer',AnnOncol, 19(6), pp. 1068-74.

Carter, P., Presta, L., Gorman, C. M., Ridgway, J. B., Henner, D., Wong, W. L., Rowland, A.

M., Kotts, C., Carver, M. E. and Shepard, H. M. (1992) 'Humanization of an anti-p185HER2antibody for human cancer therapy', Proc Natl Acad Sci U S A, 89(10), pp. 4285-9.

Cockerill, S., Stubberfield, C., Stables, J., Carter, M., Guntrip, S., Smith, K., McKeown, S.,Shaw, R., Topley, P., Thomsen, L., Affleck, K., Jowett, A., Hayes, D., Willson, M., Woollard,P. and Spalding, D. (2001) 'Indazolylamino quinazolines and pyridopyrimidines as inhibitorsof the EGFr and C-erbB-2', Bioorg Med Chem Lett, 11(11), pp. 1401-5.

Cohen, S. (1965) 'The stimulation of epidermal proliferation by a specific protein EGF ', Dev.Biol, 12, pp. 394-407.


9/12


Coussens, L., Yang-Feng, T., L., Liao, Y., Chen, E., Gray, A., McGrath, J., Seeburg, P., H.,Libermann, T., A., Schlessinger, J., Francke, U., Levinson, A. and Ullrich, A. (1985)'Tyrosine kinase receptor with extensive homology to EGFR shares chromosomal locationwith neu oncogene', Science, 230, pp. 1132-1139.

Daub, H., Weiss, F. U., Wallasch, C. and Ullrich, A. (1996) 'Role of transactivation of theEGF receptor in signalling by G-protein-coupled receptors', Nature, 379(6565), pp. 557-60.

Di Fiore, P., P., Pierce, J., H., Kraus, M., H., Segatto, O., King, C. R. and Aaronson, S., A.(1987) 'erbB-2 is a potent oncogene when overexpressed in NIH 3t3 cells ', Science, 237,pp. 178-182.

Downward, J., Yarden, Y., Mayes, E., Scrace, G., Totty, N., Stockwell, P., Ullrich, A.,Schlessing, J. and Waterfield, M., J. (1984) 'Close similarity of epidermal growth factor

receptor and v-erb-B oncogene protein sequences ', Nature, 307, pp. 521-527.

Fukushige, S., Matsubara, K., Yoshida, M., Sasaki, M., Suzuki, T., Semba, K., Toyoshima,K. and Yamamoto, T. (1986) 'Localization of a novel v-erbB-related gene, c-erbB-2, onhuman chromosome 17 and its amplification in a gastric cancer cell line', Mol Cell Biol, 6(3),pp. 955-958.

Geyer, C. E., Forster, J., Lindquist, D., Chan, S., Romieu, C. G., Pienkowski, T., Jagiello-Gruszfeld, A., Crown, J., Chan, A., Kaufman, B., Skarlos, D., Campone, M., Davidson, N.,Berger, M., Oliva, C., Rubin, S. D., Stein, S. and Cameron, D. (2006) 'Lapatinib plus

capecitabine for HER2-positive advanced breast cancer', N Engl J Med, 355(26), pp. 2733-43.

Goldman, R., Levy, R. B., Peles, E. and Yarden, Y. (1990) 'Heterodimerization of the erbB-1and erbB-2 receptors in human breast carcinoma cells: a mechanism for receptortransregulation', Biochemistry, 29(50), pp. 11024-8.

Graus-Porta, D., Beerli, R. R., Daly, J. M. and Hynes, N. E. (1997) 'ErbB-2, the preferredheterodimerization partner of all ErbB receptors, is a mediator of lateral signaling', Embo j,16(7), pp. 1647-55.

Holbro, T., Beerli, R. R., Maurer, F., Koziczak, M., Barbas, C. F., 3rd and Hynes, N. E.(2003) 'The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3to drive breast tumor cell proliferation', Proc Natl Acad Sci U S A, 100(15), pp. 8933-8.

Hudziak, R. M., Lewis, G. D., Winget, M., Fendly, B. M., Shepard, H. M. and Ullrich, A.(1989) 'p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizeshuman breast tumor cells to tumor necrosis factor', Mol Cell Biol, 9(3), pp. 1165-72.

Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q.,McMichael, J. F., Wyczalkowski, M. A., Leiserson, M. D., Miller, C. A., Welch, J. S., Walter,


10/12


M. J., Wendl, M. C., Ley, T. J., Wilson, R. K., Raphael, B. J. and Ding, L. (2013) 'Mutationallandscape and significance across 12 major cancer types', Nature, 502(7471), pp. 333-9.

King, C. R., Kraus, M. H. and Aaronson, S. A. (1985) 'Amplification of a novel v-erbB-relatedgene in a human mammary carcinoma', Science, 229(4717), pp. 974-6.

Lin, N. U., Carey, L. A., Liu, M. C., Younger, J., Come, S. E., Ewend, M., Harris, G. J., Bullitt,E., Van den Abbeele, A. D., Henson, J. W., Li, X., Gelman, R., Burstein, H. J., Kasparian, E.,Kirsch, D. G., Crawford, A., Hochberg, F. and Winer, E. P. (2008) 'Phase II trial of lapatinibfor brain metastases in patients with human epidermal growth factor receptor 2-positivebreast cancer', J Clin Oncol, 26(12), pp. 1993-9.

Lu, J., Guo, H., Treekitkarnmongkol, W., Li, P., Zhang, J., Shi, B., Ling, C., Zhou, X., Chen,T., Chiao, P. J., Feng, X., Seewaldt, V. L., Muller, W. J., Sahin, A., Hung, M. C. and Yu, D.

(2009) '14-3-3zeta Cooperates with ErbB2 to promote ductal carcinoma in situ progressionto invasive breast cancer by inducing epithelial-mesenchymal transition', Cancer Cell, 16(3),pp. 195-207.

Luttrell, L. M., Della Rocca, G. J., van Biesen, T., Luttrell, D. K. and Lefkowitz, R. J. (1997)'Gbetagamma subunits mediate Src-dependent phosphorylation of the epidermal growthfactor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation', J BiolChem, 272(7), pp. 4637-44.

Montemurro, F., Donadio, M., Clavarezza, M., Redana, S., Jacomuzzi, M. E., Valabrega, G.,

Danese, S., Vietti-Ramus, G., Durando, A., Venturini, M. and Aglietta, M. (2006) 'Outcome ofpatients with HER2-positive advanced breast cancer progressing during trastuzumab-basedtherapy', Oncologist, 11(4), pp. 318-24.

Okano, J., Gaslightwala, I., Birnbaum, M. J., Rustgi, A. K. and Nakagawa, H. (2000)'Akt/protein kinase B isoforms are differentially regulated by epidermal growth factorstimulation', J Biol Chem, 275(40), pp. 30934-42.

Riese, D. J., 2nd and Stern, D. F. (1998) 'Specificity within the EGF family/ErbB receptorfamily signaling network', Bioessays, 20(1), pp. 41-8.

Romond, E. H., Perez, E. A., Bryant, J., Suman, V. J., Geyer, C. E., Jr., Davidson, N. E.,Tan-Chiu, E., Martino, S., Paik, S., Kaufman, P. A., Swain, S. M., Pisansky, T. M.,Fehrenbacher, L., Kutteh, L. A., Vogel, V. G., Visscher, D. W., Yothers, G., Jenkins, R. B.,Brown, A. M., Dakhil, S. R., Mamounas, E. P., Lingle, W. L., Klein, P. M., Ingle, J. N. andWolmark, N. (2005) 'Trastuzumab plus adjuvant chemotherapy for operable HER2-positivebreast cancer', N Engl J Med, 353(16), pp. 1673-84.

Ross, J. S., Slodkowska, E. A., Symmans, W. F., Pusztai, L., Ravdin, P. M. and Hortobagyi,G. N. (2009) 'The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2

therapy and personalized medicine', Oncologist, 14(4), pp. 320-68.


11/12


Rusnak, D. W., Affleck, K., Cockerill, S. G., Stubberfield, C., Harris, R., Page, M., Smith, K.J., Guntrip, S. B., Carter, M. C., Shaw, R. J., Jowett, A., Stables, J., Topley, P., Wood, E. R.,Brignola, P. S., Kadwell, S. H., Reep, B. R., Mullin, R. J., Alligood, K. J., Keith, B. R., Crosby,

R. M., Murray, D. M., Knight, W. B., Gilmer, T. M. and Lackey, K. (2001) 'Thecharacterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy forcancer', Cancer Res, 61(19), pp. 7196-203.

Schechter, A. L., Stern, D. F., Vaidyanathan, L., Decker, S. J., Drebin, J. A., Greene, M. I.and Weinberg, R. A. (1984) 'The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen', Nature, 312(5994), pp. 513-6.

Semba, K., Kamata, N., Toyoshima, L. and Yamamoto, T. (1985) 'A v-erbB-relatedprotooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor geneand is amplified in a human salivary gland adenocarcinoma', Proc. Natl. Acad. Sci. USA, 82,pp. 6497-6501.

Shewchuk, L., Hassell, A., Wisely, B., Rocque, W., Holmes, W., Veal, J. and Kuyper, L. F.(1999) 'Binding Mode of the 4-Anilinoquinazoline Class of Protein Kinase Inhibitor: X-rayCrystallographic Studies of 4-Anilinoquinazolines Bound to Cyclin-Dependent Kinase 2 andp38 Kinase', Journal of Medicinal Chemistry, 43(1), pp. 133-138.

Slamon, D., J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A. and McGuire, W. L. (1987)'Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene', Science, 235(4785), pp. 177-82.

Slamon, D., J., Godolphin, W., Jones, L., A., Holt, J. A., Wong, S., G., Keith, D., E., Levin,W., J., Stuart, S., G., Udove, J., Ullrich, A. and Press, M., F. (1989) 'Studies of the HER-2/neuproto-oncogene in human breast and ovarian cancer', Science, 244, pp. 707-712.

Vermeer, P. D., Bell, M., Lee, K., Vermeer, D. W., Wieking, B. G., Bilal, E., Bhanot, G.,Drapkin, R. I., Ganesan, S., Klingelhutz, A. J., Hendriks, W. J. and Lee, J. H. (2012) 'ErbB2,EphrinB1, Src kinase and PTPN13 signaling complex regulates MAP kinase signaling inhuman cancers', PLoS One, 7(1), p. e30447.

Wainberg, Z. A., Anghel, A., Desai, A. J., Ayala, R., Luo, T., Safran, B., Fejzo, M. S., Hecht,J. R., Slamon, D. J. and Finn, R. S. (2010) 'Lapatinib, a dual EGFR and HER2 kinaseinhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergisticwith trastuzumab in vitro and in vivo', Clin Cancer Res, 16(5), pp. 1509-19.

Xia, W., Gerard, C. M., Liu, L., Baudson, N. M., Ory, T. L. and Spector, N. L. (2005)'Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosinekinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells', Oncogene, 24(41), pp. 6213-21.


12/12


Yamamoto, T., Ikawa, S., Akiyama, T., Semba, K., Nomura, N., Miyajima, N., Saito, T. andToyoshima, K. (1986) 'Similarity of protein encoded by human c-erb-B-2 gene to epidermalgrowth factor receptor', Nature, 319, pp. 230-234.

Yarden, Y. and Pines, G. (2012) 'The ERBB network: at last, cancer therapy meets systemsbiology', Nat Rev Cancer, 12(8), pp. 553-63.

Yarden, Y. and Sliwkowski, M. X. (2001) 'Untangling the ErbB signalling network', Nat RevMol Cell Biol, 2(2), pp. 127-37.

Yokota, J., Yamamoto, T., Toyoshima, K., Terada, M., Sugimura, T., Battifora, H. and Cline,M. J. (1986) 'Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo',Lancet, 1(8484), pp. 765-7.

Yu, D. H. and Hung, M. C. (1991) 'Expression of activated rat neu oncogene is sufficient toinduce experimental metastasis in 3T3 cells', Oncogene, 6(11), pp. 1991-6.

Documents

The role of overexpression of the ERBB2 (HER2/NEU) oncogene in cancer development and how it has been exploited to improve cancer treatment