Skip to main content
Log in

Epidermal growth factor receptor and c-erbB-2 expression in normal breast tissue during the menstrual cycle

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

Summary

EGF receptor (EGF-R) and c-erbB-2 are homologous tyrosine kinase transmembrane receptors. They are involved in controlling proliferation, and probably differentiation, of normal breast epithelial cells, and their expression has been linked to the prognosis of breast cancer. Their physiological roles in normal breast tissue remain to be elucidated, as most studies to date have involved breast cancer cell lines. We studied the location of EGF-R and c-erbB-2 in 100 samples of normal breast with standard immunohistochemical methods and double-labelling techniques. EGF-R was mainly expressed on the stroma and myoepithelial cells, whereas c-erbB-2 expression was exclusively epithelial. An image analyser was used to quantitate variations in their expression during the mentrual cycle. EGF-R and c-erbB-2 expression on epithelial cells was stronger during the luteal phase than the follicular phase (p < 0.01 for EGF-R). The pattern of expression was also compared with that in 28 breast cancers and 7 fibroadenomas.

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

References

  1. Dickson RB, Lippman ME: Estrogen regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocrine Reviews 8: 29–43, 1986

    Google Scholar 

  2. Bates SE, Valverius EM, Ennis BW, Bronzert DA, Sheridan JP, Stampfer MR, Mendelsohn J, Lippman ME, Dickson R: Expression of the transforming growth factor-α-epidermal growth receptor pathway in normal human breast epithelial cells. Endocrinology 126: 596–607, 1990

    PubMed  Google Scholar 

  3. Derynck R: Transforming growth factor α. Cell 54: 593–595, 1988

    PubMed  Google Scholar 

  4. Damjanov I, Mildner B, Knowles DBB: Immunohistochemical localization of the epidermal growth factor receptor in normal human tissues. Lab Invest 55: 588–592, 1986

    PubMed  Google Scholar 

  5. Velu TJ: Structure, function and transforming potential of the epidermal growth factor (review). Mol Cell Endoc 70: 205–216, 1990

    Google Scholar 

  6. Sainsbury JRC, Malcolm AJ, Appleton DR, Farndon JR, Harris AL: Presence of epidermal growth factor receptor as an indicator of prognosis in patients with breast cancer. J Clin Path 38: 1225–1228, 1985

    PubMed  Google Scholar 

  7. Fitzpatrick SL, Brightwell J, Wittliff JL, Barrows GH, Schultz GS: Epidermal growth factor binding by breast tumor biopsies and relationship to estrogen receptor and progestin receptor levels. Cancer Res 44: 3348–3353, 1984

    PubMed  Google Scholar 

  8. Murphy LJ, Sutherland RL, Stead B, Murphy LC, Laganes L: Progestin regulation of epidermal growth factor receptor in human mammary carcinoma cells. Cancer Res 46: 728–734, 1986

    PubMed  Google Scholar 

  9. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, Shepard HM, Lerang WJ, Wood WI, Goeddel DAV, Vandlen RL: Identification of heregulin, a specific activator of p185erbB-2. Science 256: 1205–1209, 1992

    PubMed  Google Scholar 

  10. Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Levy RB, Yarden Y: Isolation of the Neu/Her-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell 69: 205–216, 1992

    PubMed  Google Scholar 

  11. Quian X, Decker SJ, Greene MI: p185c-neu and epidermal growth factor receptor associate into a structure composed of activated kinases. Proc Natl Acad Sci 89: 1330–1334, 1992

    PubMed  Google Scholar 

  12. Spivak-Kroizman R, Rotin D, Pinchasi D, Ullrich A, Schelninger J, Lax I: Heterodimerization of c-erbB-2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. J Biol Chem 267: 8056–8063, 1992

    PubMed  Google Scholar 

  13. Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA: erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 230: 1854–1866, 1987

    Google Scholar 

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

    PubMed  Google Scholar 

  15. Guérin M, Gubillot M, Mathieu MC, Trangli JP, Spielmann M, Andrieu N, Riou G: Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: prognostic significance. Int J Cancer 43: 201–208, 1989

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  17. Pierce JH, Arnstein P, Di Marco E, Artaip J, Kraus MH, Leonardo F, Di Fiore PP, Aaronson SA: Oncogenic potential oferbB-2 in human mammary epithelial cells. Oncogene 6: 1189–1194, 1991

    PubMed  Google Scholar 

  18. Dati C, Antoniotti S, Taverna P, Perrotan I, De Bortoli M: Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancer cells. Oncogene 5: 1001–1006, 1990

    PubMed  Google Scholar 

  19. Read LD, Keith D, Slamon DJ, Katzenellenbogen BS: Hormonal modulation of HER-2/neu proto-oncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res 50: 3937–3951, 1990

    Google Scholar 

  20. Russell KS, Hung M-C: Transcriptional repression of theneu protooncogene by estrogen stimulated estrogen receptor. Cancer Res 52: 6624–6629, 1992

    PubMed  Google Scholar 

  21. Bacus SS, Kiguchi K, Chin D, King CR, Huberman E: Differentiation of cultured human breast cancer cells (Au-565 and MCF-7) associated with loss of cell surface HER-2/neu antigen. Mol Carcinog 3: 350–362, 1990

    PubMed  Google Scholar 

  22. Tsutsumi Y, Naber SP, De Lellis RA, Wolfe HJ, Marks PL, McKenzie SJ, Yin S: Neu oncogene protein and epidermal growth factor receptor are independently expressed in benign and malignant breast tissues. Hum Pathol 21: 750–758, 1990

    PubMed  Google Scholar 

  23. Barker S, Panahy C, Puddefoot JR, Goode AW, Vinson GP: Epidermal growth factor receptor and oestrogen receptors in the non-malignant part of the cancerous breast. Br J Cancer 60: 673–677, 1989

    PubMed  Google Scholar 

  24. Wang D, Fuji S, Konishi I, Nambu Y, Iwai T, Nonogaki H: Expression of c-erbB-2 protein and epidermal growth factor receptor in normal tissues of the genital tract and in the placenta. Virchows Archiv A Pathol Anat 420: 385–393, 1992

    Google Scholar 

  25. Giudice LC: Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine. Fertil Steril 61: 1–17, 1994

    PubMed  Google Scholar 

  26. Press MF, Cordon-Cardo C, Slamon DJ: Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 5: 953–962, 1990

    PubMed  Google Scholar 

  27. Kraus MJ, Popescu NC, Amsbaugh SC, King LR: Overexpression of the EGF receptor-related proto-oncogeneerbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J 6: 605–610, 1987

    PubMed  Google Scholar 

  28. Dittadi R, Donisi M, Brazzale A, Cappelloza L, Bruscagnin G, Gion M: Epidermal growth factor receptor in breast cancer. Comparison with non malignant breast tissue. Br J Cancer 67: 7–9, 1993

    PubMed  Google Scholar 

  29. Wärri AM, Laine AM, Majasuo KE, Alitalo KK, Harkonen PL: Estrogen suppression oferbB-2 is associated with increased growth rate of ZR-75-1 human breast cancer cellsin vitro and in nude mice. Int J Cancer 49: 616–623, 1991

    PubMed  Google Scholar 

  30. Taverna D, Antonietti S, Maggiora P, Dati C, De Bortoli M, Hynes NE: erbB-2 expression in estrogen receptor positive breast tumor cells is regulated by growth modulatory reagents. Int J Cancer 56: 522–528, 1994

    PubMed  Google Scholar 

  31. Marth C, Lang T, Cronauer MV, Doppler W, Zeimet AG, Bachmair F, Ullrich A, Daxenbichler M: Epidermal growth factor reduces HER-2 protein level in human ovarian carcinoma cells. Int J Cancer 52: 311–316, 1992

    PubMed  Google Scholar 

  32. Dougall WC, Qian X, Creene MI: Interaction of the Neu/p185 and EGF-R tyrosine kinases: implications for cellular transformation and tumor therapy. J Cell Biochem 53: 61–73, 1993

    PubMed  Google Scholar 

  33. Bradbury JM, Arno J, Edwards AW: Induction of epithelial abnormalities that resemble human breast lesions by the expression of the neu/erbB-2 oncogene in reconstituted mouse mammary gland. Oncogene 8: 1551–1558, 1993

    PubMed  Google Scholar 

  34. Kornilova ES, Taverna D, Hoeck W, Hynes NE: Surface expression of erbB-2 protein is post-transcriptionally regulated in mammary epithelial cells by epidermal growth factor and by the culture density. Oncogene 7: 511–519, 1992

    PubMed  Google Scholar 

  35. Gardner GM, Vernier G, Kirkland JL, Stancel GM: Regulation of uterine epidermal growth factor (EGF) receptors by estrogen in the mature rat and during the estrous cycle. J Steroid Biochem 32: 339–343, 1989

    PubMed  Google Scholar 

  36. Ferguson DJP, Anderson TJ: Morphological evaluation of cell turnover in relation to the menstrual cycle in the ‘resting’ human breast. Br J Cancer 44: 177–181, 1981

    PubMed  Google Scholar 

  37. Longacre TA, Bartow SA: A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol 10: 382–393, 1986

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gompel, A., Martin, A., Simon, P. et al. Epidermal growth factor receptor and c-erbB-2 expression in normal breast tissue during the menstrual cycle. Breast Cancer Res Tr 38, 227–235 (1996). https://doi.org/10.1007/BF01806677

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01806677

Key words

Navigation