Skip to main content
SpringerLink
Log in

Biological and clinical significance of her2 overexpression in Breast Cancer

  • Review Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

The product of the HER2/neu proto-oncogene, HER2, is the second member of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors and has been suggested to be a ligand orphan receptor. Ligand-dependent heterodimerization between HER2 and another HER family member, HER1, HER3 or HERA, activates the HER2 signaling pathway. The intracellular signaling pathway of HER2 is thought to involve ras-MAPK, MAPK-independent S6 kinase and phospholipase C-γ signaling pathways. However, the biological consequences of the activation of these pathways are not yet completely known.

Amplification of the HER2 gene and overexpression of the HER2 protein induces cell transformation and has been demonstrated in 10% to 40% of human breast cancer. HER2 overexpression has been suggested to associate with tumor aggressiveness, prognosis and responsiveness to hormonal and cytotoxic agents in breast cancer patients. These findings indicate that HER2 is an appropriate target for tumor-specific therapies. A number of approaches have been investigated: (1) a humanized monoclonal antibody against HER2, rhuMAbHE/?2 (trastuzumab), which is already approved for clinical use in the treatment of patients with metastatic breast cancer; (2) tyrosine kinase inhibitors, such as emodin, which block HER2 phosphorylation and its intracellular signaling; (3) active immunotherapy, such as vaccination; and (4) heat shock protein (Hsp) 90-associated signal inhibitors, such as radicicol derivatives, which induce degradation of tyrosine kinase receptors, such as HER2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

HER:

Human epidermal growth factor receptor

Hsp:

Heat shock protein

RTK:

Receptor tyrosine kinase

ECD:

Extracellular domain

PI3K:

Phosphatidylinositol 3-kinase

MAPK:

Mitogen-activated protein kinase

PLC:

Phospholipase C

EGF:

Epidermal growth factor

HB-EGF:

Heparin binding EGF-like growth factor

PCR:

Polymerase chain reaction

FISH:

Fluoroscene in silu hybridization

MAb:

Monoclonal antibody

ER:

Estrogen receptor

References

  1. Yamamoto T, Ikawa S, Akiyama T,et al: Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor.Nature 319:230–234, 1986.

    Article  PubMed  CAS  Google Scholar 

  2. Ullrich A, Coussens L, Hayflick JS,et al: Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.Nature 309:418–425, 1984.

    Article  PubMed  CAS  Google Scholar 

  3. Kraus MH, Issing W, Miki T,et al: Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors.Proc Natl Acad Sci USA 86:9193–9197, 1989.

    Article  PubMed  CAS  Google Scholar 

  4. Plowman GD, Green JM, Culouscou JM,et al: Heregulin induces tyrosine phosphorylation o.HER4/ P180erbB4.Nature 366:473–475, 1993.

    Article  CAS  Google Scholar 

  5. van der Geer P, Hunter T, Lindberg RA: Receptor pro-tein-tyrosine kinases and their signal transduction pathways.Annu Rev Cell Biol 10:251–337, 1994.

    Article  PubMed  CAS  Google Scholar 

  6. Pelicci G, Lanfrancone L, Grignani F,et al: A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.Cell 70:93–104 1992.

    Article  PubMed  CAS  Google Scholar 

  7. Lowenstein EJ, Daly RJ, Batzer AG,et al: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling.Cell 70:431–442, 1992.

    Article  PubMed  CAS  Google Scholar 

  8. Fedi P, Pierce JH, di Fiore PP,et al: Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase C gamma or GTPase-activating protein, distinguishes erbB-3 signaling from that of other ErbB/EGFR family members.Mol Cell Biol 14:492–500, 1994.

    PubMed  CAS  Google Scholar 

  9. Egan SE, Weinberg RA: The pathway to signal achievement.Nature 365:781–783, 1993.

    Article  PubMed  CAS  Google Scholar 

  10. Ming XF, Burgering BM, Wennstrom S,et al: Activation of p70/p85 S6 kinase by a pathway independent of p21ras.Nature 371:426–429, 1994.

    Article  PubMed  CAS  Google Scholar 

  11. Peles E, Levy RB, Or E,et al: Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma.EMBO J 10:2077–2086, 1991.

    PubMed  CAS  Google Scholar 

  12. Savage CR, Inagami T, Cohen S: The primary structure of epidermal growth factor.J Biol Chem 247:7612–7621, 1972.

    PubMed  CAS  Google Scholar 

  13. Higashiyama S, Abraham JA, Miller J,et al: A heparin- binding growth factor secreted by macrophage-like cells that is related to EGF.Science 251:936–939, 1991.

    Article  PubMed  CAS  Google Scholar 

  14. Shing Y, Christofori G, Hanahan D,et al: Betacellulin: a mitogen from pancreatic beta cell tumors.Science 259:1604–1607, 1993.

    Article  PubMed  CAS  Google Scholar 

  15. Peles E, Bacus SS, Koski RA,et al: Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells.Cell 69:205–216, 1992.

    Article  PubMed  CAS  Google Scholar 

  16. Goldman R, Levy RB, Peles E,et al: Heterodimeriza- tion of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: a mechanism for receptor transregulation.Biochemistry 29:11024–11028, 1990.

    Article  PubMed  CAS  Google Scholar 

  17. Graus-Porta D, Beerli RR, Daly JM,et al: erbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling.EMBO J 16:1647–1655, 1997.

    Article  PubMed  CAS  Google Scholar 

  18. Di Fiore PP, Pierce JH, Kraus MH,et al:erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells.Science 237:178–182, 1987.

    Article  PubMed  CAS  Google Scholar 

  19. Zhai YF, Beittenmiller H, Wang B,et al: Increased expression of specific protein tyrosine phosphatases in human breast epithelial cells neoplastically trans- formed by the neu oncogene.Cancer Res 53:2272–2278 1993.

    PubMed  CAS  Google Scholar 

  20. Muller WJ, Sinn E, Pattengale PK,et al: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene.Cell 54:105–115, 1988.

    Article  PubMed  CAS  Google Scholar 

  21. Andrechek ER, Hardy WR, Siegel PM,et al: Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis.Proc Natl Acad Sci USA 97:3444–3449, 2000.

    Article  PubMed  CAS  Google Scholar 

  22. Menard S, Tagliabue E, Campiglio M,et al: Role o.HER2 gene overexpression in breast carcinoma.J Cell Physiol 182:150–162, 2000.

    CAS  Google Scholar 

  23. Pauletti G, Godolphin W, Press MF,et al: Detection and quantitation o.HER-2/neu gene amplification in human breast cancer archival material using fluores- cence in situ hybridization.Oncogene 13:63–72, 1996.

    CAS  Google Scholar 

  24. Sauter G, Feichter G, Torhorst J,et al: Fluorescence in situ hybridization for detecting erbB-2 amplification in breast tumor fine needle aspiration biopsies.Acta Cytol 40:164–173, 1996.

    PubMed  CAS  Google Scholar 

  25. Busmanis I, Feleppa F, Jones A,et al: Analysis of cerbB2 expression using a panel of 6 commercially available antibodies.Pathology 26:261–267, 1994.

    Article  PubMed  CAS  Google Scholar 

  26. Roche PC, Ingle JN: Increase.HER2 with U.S. Food and Drug Administration-approved antibody.J Clin Oncol 17:434, 1999.

    CAS  Google Scholar 

  27. Carter P, Presta L, Gorman CM,et al: Humanization of an anti-pl85HER2 antibody for human cancer ther- apy.Proc Natl Acad Sci USA 89:4285–4289, 1992.

    Article  PubMed  CAS  Google Scholar 

  28. Baselga J, Tripathy D, Mendelsohn J,et al: Phase II study of weekly intravenous recombinant humanized anti-pl85HER2 monoclonal antibody in patients wit.HER2/neu-overexpressing metastatic breast cancer.J Clin Oncol 14:737–744, 1996.

    CAS  Google Scholar 

  29. J, Norton L, Albanell J,et al: Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin agains.HER2/neu overexpressing human breast cancer xenografts.Cancer Res 58:2825–2831, 1998.

    Google Scholar 

  30. Pegram MD, Lipton A, Hayes DF,et al: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-pl85HER2/neu monoclonal antibody plus cisplatin in patients wit.HER/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment.J Clin Oncol 16:2659–2671, 1998.

    CAS  Google Scholar 

  31. Slamon D, Leyland-Jones B, Shank S: Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy fo.HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: A randomized, multinational con- trolled phase III trial.Proc Am Soc Clin Oncol 17:98a, 1998.

    Google Scholar 

  32. Hoang MP, Sahin AA, Ordonez NG,et al:HER-2/neu gene amplification compared wit.HER-2/neu protein overexpression and interobserver reproducibility in invasive breast carcinoma.Am J Clin Pathol 113:852–859, 2000.

    CAS  Google Scholar 

  33. Paik S, Hazan R, Fisher ER,et al: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: Prognostic significance o.erbB-2 protein overexpression in primary breast cancer.J Clin Oncol 8:103–112, 1990.

    CAS  Google Scholar 

  34. Wright C, Angus B, Nicholson S,et al: Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer.Cancer Res 49:2087–2090, 1989.

    PubMed  CAS  Google Scholar 

  35. Rosen PP, Lesser ML, Arroyo CD,et al: Immunohis-tochemical detection o.HER2/neu in patients with axillary lymph node negative breast carcinoma. A study of epidemiologic risk factors, histologic features, and prognosis.Cancer 75:1320–1326, 1995.

    CAS  Google Scholar 

  36. Bangalore L, Tanner AJ, Laudano AP,et al: Antiserum raised against a synthetic phosphotyrosine-containing peptide selectively recognizes pl85neu/ erbB-2 and the epidermal growth factor receptor.Proc Natl Acad Sci USA 89:11637–11641, 1992.

    Article  PubMed  CAS  Google Scholar 

  37. Bacus SS, Chin D, Yarden Y,et al: Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors.Am J Pathol 148:549–558, 1996.

    PubMed  CAS  Google Scholar 

  38. Read LD, Keith D, Slamon DJ,et al: Hormonal modulation o.HER-2/neu protooncogene messenger ribonucleic acid and pl85 protein expression in human breast cancer cell lines.Cancer Res 50:3947–3951, 1990.

    CAS  Google Scholar 

  39. Newman SP, Bates NP, Vernimmen D,et al: Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer.Oncogene 19:490–497, 2000.

    Article  PubMed  CAS  Google Scholar 

  40. Benz CC, Scott GK, Sarup JC,et al: Estrogen-depen- dent, tamoxifen-resistant tumorigenic growth of MCF- 7 cells transfected wit.HER2/neu. BreastCancer Res Treat 24:85–95, 1993.

    Article  CAS  Google Scholar 

  41. Tang CK, Perez C, Grunt T,et al: Involvement of heregulin-beta2 in the acquisition of the hormoneindependent phenotype of breast cancer cells.Cancer Res 56:3350–3358, 1996.

    PubMed  CAS  Google Scholar 

  42. McCann AH, Dervan PA, O’Regan M,et al: Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer.Cancer Res 51:3296–3303, 1991.

    PubMed  CAS  Google Scholar 

  43. Carlomagno C, Perrone F, Gallo C,et al: c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases.J Clin Oncol 14:2702–2708, 1996.

    PubMed  CAS  Google Scholar 

  44. Wright C, Nicholson S, Angus B,et al: Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer.Br J Cancer 65:118–121, 1992.

    PubMed  CAS  Google Scholar 

  45. Leitzel K, Teramoto Y, Konrad K,et al: Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer.J Clin Oncol 13:1129–1135, 1995.

    PubMed  CAS  Google Scholar 

  46. Kunisue H, Kurebayashi J, Otsuki T,et al: Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors an.HER2.Br J Cancer 82:46–51, 2000.

    Article  CAS  Google Scholar 

  47. Muss HB, Thor AD, Berry DA,et al: c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer.N Engl J Med 330:1260–1266, 1994.

    Article  PubMed  CAS  Google Scholar 

  48. Thor AD, Berry DA, Budman DR,et al: erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer.J Natl Cancer Inst 90:1346–1360, 1998.

    Article  PubMed  CAS  Google Scholar 

  49. Paik S, Bryant J, Park C,et al: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer.J Natl Cancer Inst 90:1361–1370, 1998.

    Article  PubMed  CAS  Google Scholar 

  50. Jarvinen TA, Tanner M, Rantanen V,et al: Amplification and deletion of topoisomerase IIalpha associate with erbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer.Am J Pathol 156:839–847, 2000.

    PubMed  CAS  Google Scholar 

  51. Allred DC, Clark GM, Tandon AK,et al:HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma.J Clin Oncol 10:599–605, 1992.

    PubMed  CAS  Google Scholar 

  52. Gusterson BA, Gelber RD, Goldhirsch A,et al: Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group.J Clin Oncol 10:1049–1056, 1992.

    PubMed  CAS  Google Scholar 

  53. Menard S, Valagussa P, Pilotti S,et al:HER2 overexpression and response to CMF in lymph node-positive breat cancer.Proc Am Soc Clin Oncol 18:69a, 1999.

    Google Scholar 

  54. Baselga J, Seidman AD, Rosen PP,et al:HER2 over-expression and paclitaxel sensitivity in breast cancer: therapeutic implications.Oncology (Huntingt) 11 (Suppl2): 43–48, 1997.

    PubMed  CAS  Google Scholar 

  55. Disis ML, Cheever MA:HER-2/neu protein: a target for antigen-specific immunotherapy of human cancer.Adv Cancer Res 71:343–371, 1997.

    Article  PubMed  CAS  Google Scholar 

  56. Jinno H, Ueda M, Enomoto K,et al: Effectiveness of an adriamycin immunoconjugate that recognizes the c-erbB-2 product on breast cancer cell lines.Surg Today 26:501–507, 1996.

    Article  PubMed  CAS  Google Scholar 

  57. Lewis GD, Figari I, Fendly B,et al: Differential responses of human tumor cell lines to antipl85HER2 monoclonal antibodies.Cancer Immunol Immunother 37:255–263, 1993.

    Article  PubMed  CAS  Google Scholar 

  58. Burstein HJ, Kuter I, Richardson PG,et al: Herceptin and vinorelbine fo.HER2-positive metastatic breast cancer: a phase II study.Proc Am Soc Clin Oncol 19:102a, 2000.

    Google Scholar 

  59. Zhang L, Chang CJ, Bacus SS,et al: Suppressed transformation and induced differentiation o.HER-2/neu-overexpressing breast cancer cells by emodin.Cancer Res 55:3890–3896, 1995.

    CAS  Google Scholar 

  60. Zhang L, Lau YK, Xia W,et al: Tyrosine kinase inhibitor emodin suppresses growth o.HER-2/neu- overexpressing breast cancer cells in athymic mice and sensitizes these cells to the inhibitory effect of paclitaxel.Clin Cancer Res 5:343–353, 1999.

    CAS  Google Scholar 

  61. Disis ML, Calenoff E, McLaughlin G,et al: Existent T-cell and antibody immunity t.HER-2/neu protein in patients with breast cancer.Cancer Res 54:16–20, 1994.

    CAS  Google Scholar 

  62. Disis ML, Pupa SM, Gralow JR,et al: High-tite.HER- 2/neu protein-specific antibody can be detected in patients with early-stage breast cancer.J Clin Oncol 15:3363–3367, 1997.

    CAS  Google Scholar 

  63. Whitesell L, Mimnaugh EG, De Costa B,et al: Inhibition of heat shock protein HSP90-pp60v-src hetero- protein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation.Proc Natl Acad Sci USA 91:8324–8328, 1994.

    Article  PubMed  CAS  Google Scholar 

  64. Sharma SV, Agatsuma T, Nakano H: Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol.Oncogene 16:2639–2645, 1998.

    Article  PubMed  CAS  Google Scholar 

  65. Kelland LR, Sharp SY, Rogers PM,et al: DT- Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90.J Natl Cancer Inst 91:1940–1949, 1999.

    Article  PubMed  CAS  Google Scholar 

  66. Soga S, Neckers LM, Schulte TW,et al: KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules.Cancer Res 59:2931–2938, 1999.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Breast and Thyroid Surgery, Kawasaki Medical School, Japan

    Junichi Kurebayashi

Authors
  1. Junichi Kurebayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Kurebayashi, J. Biological and clinical significance of her2 overexpression in Breast Cancer. Breast Cancer 8, 45–51 (2001). https://doi.org/10.1007/BF02967477

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02967477

Keywords

Search

Navigation