Skip to main content
Log in

Nuclear and flow cytometric characteristics associated with overexpression of the c-erbB-2 oncoprotein in breast carcinoma

  • Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

The overexpression of the c-erbB-2 oncoprotein is now thought by most authors to be associated with adverse prognosis in breast carcinoma. In this study, we investigate the relationship between overexpression of the c-erbB-2 oncoprotein and nuclear size by morphometry in a series of 150 human breast carcinomas, comprising 65 cases of ductal carcinomain situ (DCIS) and 85 cases of invasive adenocarcinoma. The mean nuclear size for c-erbB-2 positive cases of DCIS was 54.8 µm2 and invasive carcinoma was 52.1 µm2 respectively, in contrast with 41.6 µm2 and 42.5 µm2 for c-erbB-2 negative cases of DCIS and invasive carcinoma respectively. Flow cytometric examination of DNA in a subset of 91 of these tumours showed no association between tumour cell aneuploidy and c-erbB-2 overexpression.

S-phase fraction could be calculated on 20 cases of DCIS and 48 invasive carcinomas. There was a strong association between c-erbB-2 overexpression, S-phase fraction (p<0.001) and proliferative index (p<0.001) in 20 cases of DCIS.

A weak association of S-phase fraction and c-erbB-2 overexpression was seen in 48 invasive carcinomas (p=0.047). This study confirms the subjective impression that there is a relationship between large tumour cell nuclear size and an overexpression of the c-erbB-2 oncoprotein, and also shows an association with increased tumour cell proliferation.

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

Access this article

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

References

  1. Fukushige S, Matsubara K, Yoshida M, Sasaki M, Suzuki T, Semba K, Toyoshima K, Yamamoto T: Localization of a novel v-erbB related gene c-erbB-2 on human chromosome 17, and its amplification in a gastric cancer cell line. Mol Cell Biol 6: 955–958, 1986

    PubMed  Google Scholar 

  2. Yarden Y, Ullrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem 57: 443–478, 1988

    PubMed  Google Scholar 

  3. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212, 1990

    PubMed  Google Scholar 

  4. Gullick WJ: Expression of the c-erbB-2 proto-oncogene protein in human breast cancer. Recent Results Cancer Res 113: 51–56, 1987

    Google Scholar 

  5. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712, 1989

    PubMed  Google Scholar 

  6. Lovekin C, Ellis IO, Locker A, Robertson JFR, Bell J, Nicholson R, Gullick WJ, Elston CW, Blamey RW: c-erbB-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer 63: 439–443, 1991

    PubMed  Google Scholar 

  7. Tsuda H, Hirohashi S, Shimosato Y, Hirota T, Tsugane S, Yamamoto H, Miyajima N, Toyoshima K, Yamamoto T, Yokota J, Yoshida T, Sakamoto H, Terada M, Sugimura T: Correlation between long term survival in breast cancer patients and amplification of two putative oncogene coamplification units: hst-1/int-2 and c-erbB-2/ear-1. Cancer Res 49: 3104–3108, 1989

    PubMed  Google Scholar 

  8. Tandon AK, Clark GM, Chamness GC, Ullrich A, McGuire WL: HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol 7: 1120–1128, 1989

    PubMed  Google Scholar 

  9. Wright C, Angus B, Nicholson S, Sainsburg JR, Cairns J, Gullick WJ, Kelly P, Harris AL, Horne CH: Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer. Cancer Res 49: 2087–2090, 1989

    PubMed  Google Scholar 

  10. Walker RA, Gullick WJ, Varley JM: An evaluation of immunoreactivity for c-erbB-2 protein as a marker of poor short term prognosis in breast cancer. Br J Cancer 60: 426–429, 1989

    PubMed  Google Scholar 

  11. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, Schlessinger J, Lippman ME, King CR: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of c-erbB-2 protein over-expression in primary breast cancer. J Clin Oncol 8: 103–112, 1990

    PubMed  Google Scholar 

  12. Berger MS, Locher GW, Saurer S, Gullick WJ, Waterfield MD, Groner B, Hynes NE: Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res 48: 1238–1243, 1988

    PubMed  Google Scholar 

  13. Varley JM, Swallow JE, Brammar WJ, Whittaker JL, Walker RA: Alterations in either c-erbB-2 (neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short term prognosis. Oncogene 1: 423–430, 1987

    PubMed  Google Scholar 

  14. Barnes DM: Breast cancer and a proto-oncogene: c-erbB-2 is a reliable prognostic marker. Br Med J 299: 1061–1062, 1989

    Google Scholar 

  15. Venter DJ, Tuzi NL, Kumar S, Gullick WJ: Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: Immunohistological assessment correlates with gene amplification. Lancet ii: 69–72, 1987

    Google Scholar 

  16. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire W: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182, 1987

    PubMed  Google Scholar 

  17. Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL, Altman DG: c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 63: 434–438, 1991

    PubMed  Google Scholar 

  18. Perren TJ: c-erbB-2 oncogene as a prognostic marker in breast cancer. Br J Cancer 63: 328–332, 1991

    PubMed  Google Scholar 

  19. Barnes DM, Lammie GA, Millis RR, Gullick WJ, Allen DS, Altman DG: An immunohistochemical evaluation of c-erbB-2 overexpression in human breast carcinoma. Br J Cancer 58: 448–452, 1988

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  21. Lammie GA, Barnes DM, Millis RR, Gullick WJ: An immunohistochemical study of the presence of c-erbB-2 protein in Paget's disease of the nipple. Histopathology 15: 505–514, 1989

    PubMed  Google Scholar 

  22. Walker RA, Senior PV, Jones JL, Critchley DR, Varley JM: An immunohistochemical andin situ hybridisation study of c-myc and c-erbB-2 expression in primary human breast carcinomas. J Pathol 158: 97–105, 1989

    PubMed  Google Scholar 

  23. Gusterson BA, Machin LG, Gullick WJ, Gibbs NM, Powles TJ, Price P, McKinna A, Harrison S: Immunohistochemical distribution of c-erbB-2 in infiltrating andin situ breast cancer. Int J Cancer 42: 842–845, 1988

    PubMed  Google Scholar 

  24. Van de Vijver MJ, Peterse JL, Mooi WJ, Wisman P, Lomans J, Dalesio O, Nusse R: Neu-protein overexpression in breast cancer: association with comedo-type ductal carcinomain situ and limited prognostic value in stage II breast cancer. N Eng J Med 319: 1239–1245, 1988

    Google Scholar 

  25. Ramachandra S, Machin L, Ashley S, Monaghan P, Gusterson BA: Immunohistochemical distribution of c-erbB-2 inin situ breast carcinoma — a detailed morphological analysis. J Pathol 161: 7–14, 1990

    PubMed  Google Scholar 

  26. Bartkova J, Barnes DM, Millis RR, Gullick WJ: Immunohistochemical demonstration of c-erbB-2 protein in mammary ductal carcinomain situ. Hum Pathol 21: 1164–1167, 1990

    PubMed  Google Scholar 

  27. Keatings L, Sinclair J, Wright C, Corbett IP, Watchorn C, Hennessy C, Angus B, Lennard T, Horne CHW: c-erbB-2 oncoprotein expression in mammary and extramammary Paget's disease: an immunohistochemical study. Histopathology 17: 243–247, 1990

    PubMed  Google Scholar 

  28. Parkes HC, Lillycrop K, Howell A, Craig RK: c-erbB-2 mRNA expression in human breast tumours: comparison with c-erbB-2 DNA amplification and correlation with prognosis. Br J Cancer 61: 39–45, 1990

    PubMed  Google Scholar 

  29. Borg A, Linell F, Idvall I, Johansson S, Sigurasson H, Ferno M, Killander D: HER-2/neu amplification and come-do type breast carcinoma. Lancet i: 1268–1269, 1989

    Google Scholar 

  30. Cardiff RD: Cellular and molecular aspects of neoplastic progression in the mammary gland. Eur J Cancer Clin Oncol 24: 15–20, 1988

    PubMed  Google Scholar 

  31. Visscher DW, Zarbo RJ, Greenawald KA, Crissman JD: Prognostic significance of morphological parameters and flow cytometric DNA analysis in carcinoma of the breast. Pathol Annu 1: 171–210, 1990

    Google Scholar 

  32. Bacus SS, Bacus JW, Slamon DJ, Press MF: HER-2/neu oncogene expression and DNA ploidy analysis in breast cancer. Arch Pathol Lab Med 114: 164–169, 1990

    PubMed  Google Scholar 

  33. Baak JPA, Chin D, Van Diest PJ, Ortiz R, Matze-Cok P, Bacus SS: Comparative longterm prognostic value of quantitative HER-2/neu protein expression, DNA ploidy, and morphometric and clinical features in paraffin-embedded invasive breast cancer. Lab Invest 64: 215–223, 1991

    PubMed  Google Scholar 

  34. Tavassoli M, Quirke P, Farzaneh F, Lock NJ, Mayne LV, Kirkham N: c-erbB-2/c-erbA co-amplification indicative of lymph node metastasis, and c-myc amplification of high tumour grade, in human breast carcinoma. Br J Cancer 60: 505–510, 1989

    PubMed  Google Scholar 

  35. Ro J, El-Naggar A, Ro J, Blick M, Frye D, Fraschini G, Fritsche H, Hortobagyi G: c-erbB-2 amplification in node negative human breast cancer. Cancer Res 49: 6941–6944, 1989

    PubMed  Google Scholar 

  36. O'Reilly SM, Barnes DM, Camplejohn RS, Bartkova J, Gregory WM, Richards MA: The relationship between c-erbB-2 expression, S-phase fraction and prognosis in breast cancer. Br J Cancer 63: 444–446, 1991

    PubMed  Google Scholar 

  37. Marx D, Schauer A, Reiche C, May A, Ummenhofer L, Reles A, Rauschecker H, Sauer R, Schumacher M: c-erbB-2 expression in correlation to other biologic parameters of breast cancer. J Cancer Res Clin Oncol 116: 15–20, 1990

    PubMed  Google Scholar 

  38. Bacus SS, Ruby SG, Weinberg DS, Chin D, Ortiz R, Bacus JW: HER-2/neu oncogene expression and proliferation in breast cancers. Am J Path 137: 103–111, 1990

    PubMed  Google Scholar 

  39. Barnes DM, Meyer JS, Gonzalez JG, Gullick WJ, Millis RR: Relationship between c-erbB-2 immunoreactivity and thymidine labelling index in breast carcinomain situ. Breast Cancer Res Treat 18: 11–17, 1991

    PubMed  Google Scholar 

  40. Todd JH, Dowle C, Williams MR, Elston CW, Ellis IO, Hinton CP, Blamey RW, Haybittle JL: Confirmation of a prognostic index in primary breast cancer. Br J Cancer 56: 489–492, 1987

    PubMed  Google Scholar 

  41. Hedley D, Friedlander M, Taylor I: Application of DNA flow cytometry to paraffin embedded archival material for the study of aneuploidy and its clinical significance. Cytometry 6: 327–333, 1985

    PubMed  Google Scholar 

  42. Owainati AAR, Robins RA, Hinton C, Ellis IO, Dowle CS, Ferry B, Elston CW, Blamey RW, Baldwin RW: Tumour aneuploidy, prognostic parameters and survival in primary breast cancer. Br J Cancer 55: 449–454, 1987

    PubMed  Google Scholar 

  43. Baisch H, Gohde W, Linden WA: Analysis of PCP data to determine the fraction of cells in various phases of the cell cycle. Radiat Environ Biophys 12: 31–39, 1975

    PubMed  Google Scholar 

  44. Rogers LW, Page DL, Anderson TJ: Carcinomain situ (CIS). In: Page DL, Anderson TJ: Diagnostic Histopathology of the Breast. Churchill Livingstone, London, 1987, pp 157–192

    Google Scholar 

  45. Meyer JS: Cell kinetics of histologic variants ofin situ breast carcinoma. Breast Cancer Res Treat 7: 171–180, 1986

    PubMed  Google Scholar 

  46. Lagios MD, Margolin FR, Westdahl PR, Rose MR: Mammographically detected duct carcinomain situ: frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 63: 618–624, 1989

    PubMed  Google Scholar 

  47. Gentili C, Sanfilippo O, Silvestrini R: Cell proliferation and its relationship to clinical features and relapse in breast cancers. Cancer 48: 974–979, 1981

    PubMed  Google Scholar 

  48. Silvestrini R, Daidone MG, Gasparini G: Cell kinetics as a prognostic marker in node negative breast cancer. Cancer 56: 1982–1987, 1985

    PubMed  Google Scholar 

  49. Meyer JS, Coplin MD: Thymidine labeling index, flow cytometric S-phase measurement, and DNA index in human tumours. Am J Clin Pathol 89: 586–595, 1988

    PubMed  Google Scholar 

  50. Stal O, Wingren S, Carstensen J, Rutqvist LE, Skoog L, Klintenberg C, Nordenskjold B: Prognostic value of DNA ploidy and S-phase fraction in relation to estrogen receptor content and clinicopathologic variables in primary breast cancer. Eur J Cancer Clin Oncol 25: 301–309, 1989

    PubMed  Google Scholar 

  51. Lupu R, Colomer R, Zugmaier G, Sarup J, Shepard M, Slamon D, Lippman ME: Direct interaction of a ligand for the erbB-2 oncogene product with the EGF receptor and p185erbB2. Science 249: 1552–1555, 1990

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Poller, D.N., Galea, M., Pearson, D. et al. Nuclear and flow cytometric characteristics associated with overexpression of the c-erbB-2 oncoprotein in breast carcinoma. Breast Cancer Res Tr 20, 3–10 (1991). https://doi.org/10.1007/BF01833351

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01833351

Key words

Navigation