HER-2/neu in Breast Cancer: A Possible Means of Therapy?

  • T. Brodowicz
  • C. Wiltschke
  • C. C. Zielinski
Conference paper


HER-2/neu (synonyms are erbB-2, c-erbB-2) is a proto-oncogene from the erbB family located on chromosome 17q21 (Smith et al. 1993). This oncogene encodes a 185-kDa transmembrane glycoprotein with an extracellular region which is structurally similar to that of epidermal growth factor receptor and intracellular tyrosine kinase activity (Lupu et al. 1992; Harris et al. 1992). While the extracellular domain has ligand-binding activity (Staebler et al. 1994), the direct natural ligand of HER-2/neu is still unknown (Peles and Yarden 1993).


Breast Cancer Breast Cancer Cell Peripheral Blood Mononuclear Cell Hormone Receptor Status Polymerase Chain Reac 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Allred DC, O’Connell P, Fuqua SA, Osborne CK (1994) Immunohistochemical studies of early breast cancer evolution. Breast Cancer Res Treat 32:13–18PubMedCrossRefGoogle Scholar
  2. Barnes DM, Meyer JS, Gonzalez JG, Gullick WJ, Millis RR (1991) Relationship between c-erbB-2 immunoreactivity and thymidine labelling index in breast carcinoma in situ. Breast Cancer Res Treat 18:11–17PubMedCrossRefGoogle Scholar
  3. Berchuck A, Kamel A, Whitaker R, Kern B, Olt G, Kinney R, Soper JT, Dodge R, Clarke-Pearson DL, Marks P, McKenzie S, Yin S, Bast RC (1990) Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50:4087–4091PubMedGoogle Scholar
  4. Frank H, Valone FH, Kaufman PA, Guyre PM, Lewis LD, Memoli V, Deo Y, Graziano R, Fisher JL, Meyer L, Mrozek-Orlowski M, Wardwell K, Guyre V, Morley TL, Arvizu C, Fanger MW (1995) Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the protooncogene HER-2/neu. J Clin Oncol 13:2281–2292Google Scholar
  5. Gatanaga T, Hwang C, Kohr W (1990) Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients. Proc Natl Acad Sci USA 87:8781–8784PubMedCrossRefGoogle Scholar
  6. Gavin JG III, Buell DN, Roth J (1972) Water-soluble insulin receptors from human lymphocytes. Science 178:168–169PubMedCrossRefGoogle Scholar
  7. Harris AL, Nicholson S, Sainsbury R, Wright C, Farndon J (1992) Epidermal growth factor receptor and other oncogenes as prognostic markers. Monogr Natl Cancer Inst 11:181–187PubMedGoogle Scholar
  8. Harwerth IM, Wels W, Marte BM, Hynes NE (1992) Monoclonal antibodies against the extracellular domain of the erbB-2 receptor function as partial ligand agonists. J Biol Chem 267:15160–15167PubMedGoogle Scholar
  9. Harwerth IM, Wels W, Schlegel J, Muller M, Hynes NE (1993) Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. Br J Cancer 68:1140–1145PubMedCrossRefGoogle Scholar
  10. Horiguchi J, Lino Y, Takei H, Yokoe T, Ishida T, Morishita Y (1994) Immunohistochemical study on the expression of c-erbB-2 oncoprotein in breast cancer. Oncology 51: 47–51PubMedCrossRefGoogle Scholar
  11. Hurwitz E, Stancovski I, Sela M, Yarden Y (1995) Suppression and promotion of tumor growth by monoclonal antibodies to erbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci USA 92:3353–3357PubMedCrossRefGoogle Scholar
  12. Isola J J, Holli K, Oksa H, Teramoto Y, Kallioniemi OP (1994) Elevated erbB-2 oncoprotein levels in preoperative and follow-up serum samples define an aggressive disease course in patients with breast cancer. Cancer 73:652–658PubMedCrossRefGoogle Scholar
  13. Kallioniemi OP, Holli K, Visakorpi T, Koivula T, Helin HH, Isola JJ (1991) Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 49:650–655PubMedCrossRefGoogle Scholar
  14. Kandl H, Seymour L, Bezwoda WR (1994) Soluble c-erbB-2 fragment in serum correlates with disease stage and predicts for shortened survival in patients with earlystage and advanced breast cancer. Br J Cancer 70:739–742PubMedCrossRefGoogle Scholar
  15. Kasprzyk PG, Song SU, Di Fiore PP, King CR (1992) Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. Cancer Res 52:2771–2776PubMedGoogle Scholar
  16. Kern JA, Schwartz DA, Nordberg JE, Weiner DB, Greene MI, Torney L, Robinson RA (1990) p185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res 50:5184–5191PubMedGoogle Scholar
  17. Kynast B, Binder L, Marx D, Zoll B, Schmoll HJ, Oellerich M, Schauer A (1993) Determination of a fragment of the c-erbB-2 translational product pi85 in serum of breast cancer patients. J Cancer Res Clin Oncol 119:249–252PubMedCrossRefGoogle Scholar
  18. Leitzel K, Teramoto Y, Sampson E, Mauceri J, Langton BC, Demers L, Podczaski E, Harvey H, Shambaugh S, Volas G, Weaver S, Lipton A (1992) Elevated soluble c-erbB-2 antigen levels in the serum and effusions of a proportion of breast cancer patients. J Clin Oncol 10:1436–1443PubMedGoogle Scholar
  19. Lewis GD, Figari I, Fendly B, Wong WL, Carter P, Gorman C, Shepard HM (1993) Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 37:255–263PubMedCrossRefGoogle Scholar
  20. Lupu R, Colomer R, Kannan B, Lippman ME (1992) Characterization of a growth factor that binds exclusively to the erbB-2 receptor and induces cellular responses. Proc Natl Acad Sci USA 89:2287–2291PubMedCrossRefGoogle Scholar
  21. Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson IC (1994) c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330:1260–1266PubMedCrossRefGoogle Scholar
  22. Narita T, Funahashi H, Satoh Y, Takagi H (1993) c-erbB-2 protein in the sera of breast cancer patients. Breast Cancer Res Treat 24:97–102CrossRefGoogle Scholar
  23. O’Reilly SM, Barnes DM, Camplejohn RS, Bartkova J, Gregory WM, Richards MA (1991) The relationship between c-erbB-2 expression, S-phase fraction and prognosis in breast cancer. Br J Cancer 63:444–446PubMedCrossRefGoogle Scholar
  24. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, Schlessinger J, Lippman ME, King CR (1990) Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 8:103–112PubMedGoogle Scholar
  25. Park JW, Hong K, Carter P, Asgari H, Guo LY, Keller GA, Wirth C, Shalaby R, Kotts C, Wood WI, Papahadjopoulos D, Benz CC (1995) Development of anti-pi85HER2 immunoliposomes for cancer therapy. Proc Natl Acad Sci USA 92:1327–1331PubMedCrossRefGoogle Scholar
  26. Peles E, Yarden Y (1993) Neu and its ligands: from an oncogene to neural factors. Bioessays 15:815–824PubMedCrossRefGoogle Scholar
  27. Press MF, Hung G, Godolphin W, Slamon DJ (1994) Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 54:2771–2777PubMedGoogle Scholar
  28. Pupa SM, Menard S, Morelli D, Pozzi B, De Palo G, Colnaghi MI (1993a) The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage. Oncogene 8:2917–2923PubMedGoogle Scholar
  29. Pupa SM, Menard S, Andreola S, Colnaghi MI (1993b) Antibody response against the c-erbB-2 oncoprotein in breast carcinoma patients. Cancer Res 53:5864–5866PubMedGoogle Scholar
  30. Rubin LA, Jay G, Nelson DL (1986) The released interleukin-2 receptor binds interleukin-2 efficiently. J Immunol 137:3841–3845PubMedGoogle Scholar
  31. Schonborn I, Zschiesche W, Spitzer E, Minguillon C, Mohner M, Ebeling K, Grosse R (1994) c-erbB-2 overexpression in primary breast cancer: independent prognostic factor in patients at high risk. Breast Cancer Res Treat 29:287–295Google Scholar
  32. Seshadri R, Firgaira FA, Horsfall DJ, McKaul K, Setlur V, Kitchen B (1993) Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group. J Clin Oncol 11:1936–1942PubMedGoogle Scholar
  33. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 23:177–182CrossRefGoogle Scholar
  34. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRefGoogle Scholar
  35. Smith K, Houlbrook S, Greenall M, Carmichael J, Harris AL (1993) Topoisomerase Ila co-amplification with erbB-2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity. Oncogene 8:933–938PubMedGoogle Scholar
  36. Staebler A, Sommers C, Mueller SC, Byers S, Thompson EW, Lupu R (1994) Modulation of breast cancer progression and differentiation by the gp3o/heregulin. Breast Cancer Res Treat 31:175–182PubMedCrossRefGoogle Scholar
  37. Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y, Sela M (1991) Mechanistic aspects of the opposing effects of monoclonal antibodies to the erbB-2 receptor on tumor growth. Proc Natl Acad Sci USA 88:8691–8695PubMedCrossRefGoogle Scholar
  38. Tandon AK, Clark GM, Chamness GC, Ullrich A, McGuire WL (1989) HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol 7:1120–1128PubMedGoogle Scholar
  39. Toikkanen S, Helin H, Isola J, Joensuu H (1992) Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow up. J Clin Oncol 10:1044–1048PubMedGoogle Scholar
  40. Tsai CM, Chang KT, Perng RP, Mitsudomi T, Chen MH, Kadoyama C, Gazdar AF (1993) Correlation of intrinsic chemoresistance of non-small-cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations. J Natl Cancer Inst 85:897–901PubMedCrossRefGoogle Scholar
  41. Weber W, Gill GN, Spiess J (1984) Production of an epidermal growth factor receptor-related protein. Science 224:294–297PubMedCrossRefGoogle Scholar
  42. Wiltschke C, Krainer M, Budinsky A, Berger A, Miiller C, Zeillinger R, Speiser P, Kubista E, Eibl M, Zielinski CC (1995) Reduced mitogenic stimulation of peripheral blood mononuclear cells as a prognostic parameter for the course of breast cancer: a prospective longitudinal study. Br J Cancer 71:1292–1296PubMedCrossRefGoogle Scholar
  43. Wu JT, Astill ME, Zhang P (1993) Detection of the extracellular domain of c-erbB-2 oncoprotein in sera from patients with various carcinomas: correlation with tumor markers. I Clin Lab Anal 7:31–40CrossRefGoogle Scholar
  44. Zeillinger R, Schneeberger C, Speiser P (1993) Rapid quantitative analysis of differential PCR products by high-performance liquid chromatography. Biotechniques 15:89–95PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • T. Brodowicz
  • C. Wiltschke
  • C. C. Zielinski

There are no affiliations available

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