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Gene Review

ERBB2  -  erb-b2 receptor tyrosine kinase 2

Homo sapiens

Synonyms: CD340, HER-2, HER-2/neu, HER2, MLN 19, ...
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Disease relevance of ERBB2

  • A total of 115 malignant breast tumors were analyzed by hierarchical clustering based on patterns of expression of 534 "intrinsic" genes and shown to subdivide into one basal-like, one ERBB2-overexpressing, two luminal-like, and one normal breast tissue-like subgroup [1].
  • These results demonstrate that the inhibition of morphogenesis and transcription of specific adhesion molecules in human mammary epithelial cells can be affected by signals generated by the ERBB2 receptor and suggest a role for ERBB2 overexpression in tumor progression and metastasis [2].
  • Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272 [3].
  • ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression [4].
  • Furthermore, using microarray expression profiling, we show that ERBB2 up-regulates the expression of prometastatic genes in medulloblastoma cells [5].
  • These data suggest that HER2 overexpression in HER2 2+ carcinomas is due to an accumulation of the recycled oncoprotein to the cell surface induced by activated PKCalpha [6].
  • In the latter group, 52.5% of the breast carcinomas showed basal-like differentiation (estrogen receptor, progesterone receptor, and HER2 negative) versus only 5.9% in the group irradiated during breast development (P < 0.0001) [7].
  • Taken together, we have demonstrated an increase in ERBB2 receptor activation in incompletely resected preinvasive breast cancer [8].
  • (111)In-DTPA-pertuzumab sensitively imaged HER2 downregulation after 3 d of treatment with trastuzumab and detected a reduction in viable HER2-positive tumor cells after 3 wk of therapy in MDA-MB-361 human breast cancer xenografts [9].
  • HER2 overexpression on CTC was restricted to ductal carcinomas and associated with high tumor stage (P = 0.002) [10].

Psychiatry related information on ERBB2

  • Moreover, CISH is a valuable tool for the assessment of HER2 gene status with potential prognostic value and, therefore, in clinical decision making for treatment of high-risk LNNBC [11].
  • Furthermore, c-erb-B2. c-fos and p53 appear to be important for growth and differentiation processes in human development as the occurrence of these proteins was not only restricted to specific tissues but also to specific stages of development of these tissues [12].
  • These results suggest that HER2 may potentiate tumorigenesis by inducing tumor cell resistance to host defense mechanisms [13].
  • The anti-idiotypic (Id) monoclonal antibody (MAb) 520C9-6b (IgG1k), raised in syngenic mice against the murine anti-Her2/neu MAb 520C9 (Ab1), functionally mimics a human Her2/neu epitope and serves as a surrogate for the protein antigen [14].

High impact information on ERBB2


Chemical compound and disease context of ERBB2


Biological context of ERBB2

  • PURPOSE: The aim of the study was not only to detect micrometastatic cells in bone marrow, but also to assess the expression of nuclear proliferation markers (Ki-67 and p120) and the erbB2 oncogene (also known as ERBB2) in these cells and, thus, hopefully improve prognostic precision [24].
  • To relate the effects on gene transcription to a functional ERBB2 protein, signaling from the receptor was inhibited by the antibody 4D5, which blocks phosphorylation of ERBB2 on tyrosine residues and association of the protein with the GRB2/Sem5 protein [2].
  • In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF [25].
  • As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression [26].
  • The remaining six tumors showed an increase in oncogene copy number as well as the number of chromosome 11 or 17 centromeres (the original location of CCNDI and ERBB2, respectively) [27].

Anatomical context of ERBB2


Associations of ERBB2 with chemical compounds

  • Specific expression of the pS2 gene in subclasses of breast cancers in comparison with expression of the estrogen and progesterone receptors and the oncogene ERBB2 [29].
  • No evidence for the presence of truncated forms of estrogen-receptor mRNA has been found, and overexpression of the ERBB2 oncogene did not correlate with the steroid receptor status or pS2 gene expression [29].
  • After treatment with the antibody 4D5, the ERBB2 transfectants regain the ability to form three-dimensional structures in collagen gels and the rates of transcription of the genes encoding the E-cadherin and the alpha 2 integrin subunit are restored to the levels seen in MTSV1-7neo cells [2].
  • In contrast to previous observations based on constitutively overexpressing cell lines, P21 induced by tetracycline-regulated ERBB2 localizes to the nucleus in arrested cells [20].
  • Our data suggest elevated MAPK activity results from enhanced ERBB2 expression in the LTED cells versus the wild-type (wt), and treatment with the tyrosine kinase inhibitor ZD1839 revealed increased sensitivity in both transcription and proliferation assays [30].
  • A simple defined medium containing an IGF1 analog, heregulin-1beta (a ligand for ERBB2/ERBB3), fibroblast growth factor-2 (FGF2), and activin A supported long-term growth of multiple hESC lines [31].

Physical interactions of ERBB2

  • These results also provide a molecular explanation for recent observations linking co-overexpression of coactivators and her2/neu with poor prognosis: coactivators increase SDF-1alpha expression whereas her2/neu stabilize CXCR4 protein [32].
  • We previously described Erbin as a mammalian LET-413 homologue interacting with ERBB2/HER2, an epidermal growth factor receptor family member [33].
  • We examined the contribution of the new AP-2 binding site to ERBB2 overexpression [34].
  • Neu differentiation factor (NDF) is a 44-kD glycoprotein which was isolated from ras-transformed rat fibroblasts and indirectly induces tyrosine phosphorylation of the HER-2/neu receptor via binding to either the HER-3 or HER-4 receptor [35].
  • Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma [36].

Enzymatic interactions of ERBB2


Regulatory relationships of ERBB2


Other interactions of ERBB2


Analytical, diagnostic and therapeutic context of ERBB2


  1. Repeated observation of breast tumor subtypes in independent gene expression data sets. Sorlie, T., Tibshirani, R., Parker, J., Hastie, T., Marron, J.S., Nobel, A., Deng, S., Johnsen, H., Pesich, R., Geisler, S., Demeter, J., Perou, C.M., Lønning, P.E., Brown, P.O., Børresen-Dale, A.L., Botstein, D. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Overexpression of ERBB2 in human mammary epithelial cells signals inhibition of transcription of the E-cadherin gene. D'souza, B., Taylor-Papadimitriou, J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  3. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Shimamura, T., Ji, H., Minami, Y., Thomas, R.K., Lowell, A.M., Shah, K., Greulich, H., Glatt, K.A., Meyerson, M., Shapiro, G.I., Wong, K.K. Cancer Res. (2006) [Pubmed]
  4. Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Bubendorf, L., Kononen, J., Koivisto, P., Schraml, P., Moch, H., Gasser, T.C., Willi, N., Mihatsch, M.J., Sauter, G., Kallioniemi, O.P. Cancer Res. (1999) [Pubmed]
  5. ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma. Hernan, R., Fasheh, R., Calabrese, C., Frank, A.J., Maclean, K.H., Allard, D., Barraclough, R., Gilbertson, R.J. Cancer Res. (2003) [Pubmed]
  6. Protein kinase Calpha determines HER2 fate in breast carcinoma cells with HER2 protein overexpression without gene amplification. Magnifico, A., Albano, L., Campaner, S., Campiglio, M., Pilotti, S., Ménard, S., Tagliabue, E. Cancer Res. (2007) [Pubmed]
  7. Radiation effects on development of HER2-positive breast carcinomas. Castiglioni, F., Terenziani, M., Carcangiu, M.L., Miliano, R., Aiello, P., Bertola, L., Triulzi, T., Gasparini, P., Camerini, T., Sozzi, G., Fossati-Bellani, F., Ménard, S., Tagliabue, E. Clin. Cancer Res. (2007) [Pubmed]
  8. Incomplete surgical resection of ductal carcinomas in situ results in activation of ERBB2 in residual breast cancer cells. Singer, C.F., Hudelist, G., Fuchs, E.M., Köstler, W., Fink-Retter, A., Gschwantler-Kaulich, D., Gnant, M., Lamm, W., Rudas, M., Czerwenka, K., Kubista, E. Endocr. Relat. Cancer (2009) [Pubmed]
  9. Micro-SPECT/CT with 111In-DTPA-pertuzumab sensitively detects trastuzumab-mediated HER2 downregulation and tumor response in athymic mice bearing MDA-MB-361 human breast cancer xenografts. McLarty, K., Cornelissen, B., Cai, Z., Scollard, D.A., Costantini, D.L., Done, S.J., Reilly, R.M. J. Nucl. Med. (2009) [Pubmed]
  10. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Riethdorf, S., Müller, V., Zhang, L., Rau, T., Loibl, S., Komor, M., Roller, M., Huober, J., Fehm, T., Schrader, I., Hilfrich, J., Holms, F., Tesch, H., Eidtmann, H., Untch, M., von Minckwitz, G., Pantel, K. Clin. Cancer Res. (2010) [Pubmed]
  11. Analysis of HER2 by chromogenic in situ hybridization and immunohistochemistry in lymph node-negative breast carcinoma: prognostic relevance. Peir??, G., Aranda, F.I., Adrover, E., Niveiro, M., Alenda, C., Pay??, A., Segu??, J. Hum. Pathol. (2007) [Pubmed]
  12. The oncoproteins c-erb-B2, c-fos and the tumour suppressor protein p53 in human embryos and fetuses. Miosge, N., Schneider, W., Götz, W., Herken, R. Anat. Embryol. (1997) [Pubmed]
  13. Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells. Hudziak, R.M., Lewis, G.D., Shalaby, M.R., Eessalu, T.E., Aggarwal, B.B., Ullrich, A., Shepard, H.M. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  14. Murine monoclonal anti-idiotypic antibody as a surrogate antigen for human Her-2/neu. Baral, R., Sherrat, A., Das, R., Foon, K.A., Bhattacharya-Chatterjee, M. Int. J. Cancer (2001) [Pubmed]
  15. From the molecule to the clinic--inhibiting HER2 to treat breast cancer. Eisenhauer, E.A. N. Engl. J. Med. (2001) [Pubmed]
  16. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Peles, E., Bacus, S.S., Koski, R.A., Lu, H.S., Wen, D., Ogden, S.G., Levy, R.B., Yarden, Y. Cell (1992) [Pubmed]
  17. Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. van de Vijver, M.J., Peterse, J.L., Mooi, W.J., Wisman, P., Lomans, J., Dalesio, O., Nusse, R. N. Engl. J. Med. (1988) [Pubmed]
  18. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Shin, I., Yakes, F.M., Rojo, F., Shin, N.Y., Bakin, A.V., Baselga, J., Arteaga, C.L. Nat. Med. (2002) [Pubmed]
  19. Gene expression profiling of primary breast carcinomas using arrays of candidate genes. Bertucci, F., Houlgatte, R., Benziane, A., Granjeaud, S., Adélaïde, J., Tagett, R., Loriod, B., Jacquemier, J., Viens, P., Jordan, B., Birnbaum, D., Nguyen, C. Hum. Mol. Genet. (2000) [Pubmed]
  20. Premature senescence is a primary fail-safe mechanism of ERBB2-driven tumorigenesis in breast carcinoma cells. Trost, T.M., Lausch, E.U., Fees, S.A., Schmitt, S., Enklaar, T., Reutzel, D., Brixel, L.R., Schmidtke, P., Maringer, M., Schiffer, I.B., Heimerdinger, C.K., Hengstler, J.G., Fritz, G., Bockamp, E.O., Prawitt, D., Zabel, B.U., Spangenberg, C. Cancer Res. (2005) [Pubmed]
  21. Medulloblastoma sensitivity to 17-allylamino-17-demethoxygeldanamycin requires MEK/ERKM. Calabrese, C., Frank, A., Maclean, K., Gilbertson, R. J. Biol. Chem. (2003) [Pubmed]
  22. The CGA gene as new predictor of the response to endocrine therapy in ER alpha-positive postmenopausal breast cancer patients. Bièche, I., Parfait, B., Noguès, C., Andrieu, C., Vidaud, D., Spyratos, F., Lidereau, R., Vidaud, M. Oncogene (2001) [Pubmed]
  23. Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma. Walch, A., Specht, K., Braselmann, H., Stein, H., Siewert, J.R., Hopt, U., Höfler, H., Werner, M. Int. J. Cancer (2004) [Pubmed]
  24. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. Pantel, K., Schlimok, G., Braun, S., Kutter, D., Lindemann, F., Schaller, G., Funke, I., Izbicki, J.R., Riethmüller, G. J. Natl. Cancer Inst. (1993) [Pubmed]
  25. Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha. Kalthoff, H., Roeder, C., Gieseking, J., Humburg, I., Schmiegel, W. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  26. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Sørlie, T., Perou, C.M., Tibshirani, R., Aas, T., Geisler, S., Johnsen, H., Hastie, T., Eisen, M.B., van de Rijn, M., Jeffrey, S.S., Thorsen, T., Quist, H., Matese, J.C., Brown, P.O., Botstein, D., Eystein Lønning, P., Børresen-Dale, A.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  27. Chromosomal rearrangements and oncogene amplification precede aneuploidization in the genetic evolution of breast cancer. Rennstam, K., Baldetorp, B., Kytölä, S., Tanner, M., Isola, J. Cancer Res. (2001) [Pubmed]
  28. Tissue microarrays for gene amplification surveys in many different tumor types. Schraml, P., Kononen, J., Bubendorf, L., Moch, H., Bissig, H., Nocito, A., Mihatsch, M.J., Kallioniemi, O.P., Sauter, G. Clin. Cancer Res. (1999) [Pubmed]
  29. Specific expression of the pS2 gene in subclasses of breast cancers in comparison with expression of the estrogen and progesterone receptors and the oncogene ERBB2. Rio, M.C., Bellocq, J.P., Gairard, B., Rasmussen, U.B., Krust, A., Koehl, C., Calderoli, H., Schiff, V., Renaud, R., Chambon, P. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  30. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. Martin, L.A., Farmer, I., Johnston, S.R., Ali, S., Marshall, C., Dowsett, M. J. Biol. Chem. (2003) [Pubmed]
  31. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Wang, L., Schulz, T.C., Sherrer, E.S., Dauphin, D.S., Shin, S., Nelson, A.M., Ware, C.B., Zhan, M., Song, C.Z., Chen, X., Brimble, S.N., McLean, A., Galeano, M.J., Uhl, E.W., D'Amour, K.A., Chesnut, J.D., Rao, M.S., Blau, C.A., Robins, A.J. Blood (2007) [Pubmed]
  32. The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1alpha/CXCL12. Kishimoto, H., Wang, Z., Bhat-Nakshatri, P., Chang, D., Clarke, R., Nakshatri, H. Carcinogenesis (2005) [Pubmed]
  33. Interaction between Erbin and a Catenin-related protein in epithelial cells. Jaulin-Bastard, F., Arsanto, J.P., Le Bivic, A., Navarro, C., Vély, F., Saito, H., Marchetto, S., Hatzfeld, M., Santoni, M.J., Birnbaum, D., Borg, J.P. J. Biol. Chem. (2002) [Pubmed]
  34. Identification of HTF (HER2 transcription factor) as an AP-2 (activator protein-2) transcription factor and contribution of the HTF binding site to ERBB2 gene overexpression. Vernimmen, D., Begon, D., Salvador, C., Gofflot, S., Grooteclaes, M., Winkler, R. Biochem. J. (2003) [Pubmed]
  35. Neu differentiation factor upregulates epidermal migration and integrin expression in excisional wounds. Danilenko, D.M., Ring, B.D., Lu, J.Z., Tarpley, J.E., Chang, D., Liu, N., Wen, D., Pierce, G.F. J. Clin. Invest. (1995) [Pubmed]
  36. Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma. Peles, E., Levy, R.B., Or, E., Ullrich, A., Yarden, Y. EMBO J. (1991) [Pubmed]
  37. Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Järvinen, T.A., Tanner, M., Bärlund, M., Borg, A., Isola, J. Genes Chromosomes Cancer (1999) [Pubmed]
  38. Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells. Lev, D.C., Kim, L.S., Melnikova, V., Ruiz, M., Ananthaswamy, H.N., Price, J.E. Br. J. Cancer (2004) [Pubmed]
  39. PEA3 cooperates with c-Jun in regulation of HER2/neu transcription. Matsui, K., Sugimori, K., Motomura, H., Ejiri, N., Tsukada, K., Kitajima, I. Oncol. Rep. (2006) [Pubmed]
  40. HER-2/c-erbB2 is phosphorylated by calmodulin-dependent protein kinase II on a single site in the cytoplasmic tail at threonine-1172. Feinmesser, R.L., Gray, K., Means, A.R., Chantry, A. Oncogene (1996) [Pubmed]
  41. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. Konecny, G., Pauletti, G., Pegram, M., Untch, M., Dandekar, S., Aguilar, Z., Wilson, C., Rong, H.M., Bauerfeind, I., Felber, M., Wang, H.J., Beryt, M., Seshadri, R., Hepp, H., Slamon, D.J. J. Natl. Cancer Inst. (2003) [Pubmed]
  42. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. Osborne, C.K., Bardou, V., Hopp, T.A., Chamness, G.C., Hilsenbeck, S.G., Fuqua, S.A., Wong, J., Allred, D.C., Clark, G.M., Schiff, R. J. Natl. Cancer Inst. (2003) [Pubmed]
  43. Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Su, J.L., Shih, J.Y., Yen, M.L., Jeng, Y.M., Chang, C.C., Hsieh, C.Y., Wei, L.H., Yang, P.C., Kuo, M.L. Cancer Res. (2004) [Pubmed]
  44. Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. Ueda, Y., Wang, S., Dumont, N., Yi, J.Y., Koh, Y., Arteaga, C.L. J. Biol. Chem. (2004) [Pubmed]
  45. Molecular mechanism for SHP2 in promoting HER2-induced signaling and transformation. Zhou, X., Agazie, Y.M. J. Biol. Chem. (2009) [Pubmed]
  46. ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer. Petry, I.B., Fieber, E., Schmidt, M., Gehrmann, M., Gebhard, S., Hermes, M., Schormann, W., Selinski, S., Freis, E., Schwender, H., Brulport, M., Ickstadt, K., Rahnenführer, J., Maccoux, L., West, J., Kölbl, H., Schuler, M., Hengstler, J.G. Clin. Cancer Res. (2010) [Pubmed]
  47. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Plowman, G.D., Green, J.M., Culouscou, J.M., Carlton, G.W., Rothwell, V.M., Buckley, S. Nature (1993) [Pubmed]
  48. P-glycoprotein, HER-2/neu, and mutant p53 expression in human gynecologic tumors. Schneider, J., Rubio, M.P., Barbazán, M.J., Rodriguez-Escudero, F.J., Seizinger, B.R., Castresana, J.S. J. Natl. Cancer Inst. (1994) [Pubmed]
  49. New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. Kauraniemi, P., Bärlund, M., Monni, O., Kallioniemi, A. Cancer Res. (2001) [Pubmed]
  50. Amplification of a 280-kilobase core region at the ERBB2 locus leads to activation of two hypothetical proteins in breast cancer. Kauraniemi, P., Kuukasjärvi, T., Sauter, G., Kallioniemi, A. Am. J. Pathol. (2003) [Pubmed]
  51. Identification and validation of an ERBB2 gene expression signature in breast cancers. Bertucci, F., Borie, N., Ginestier, C., Groulet, A., Charafe-Jauffret, E., Adélaïde, J., Geneix, J., Bachelart, L., Finetti, P., Koki, A., Hermitte, F., Hassoun, J., Debono, S., Viens, P., Fert, V., Jacquemier, J., Birnbaum, D. Oncogene (2004) [Pubmed]
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