Article Data

  • Views 435
  • Dowloads 110

Original Research

Open Access

Immunoexpression of HER family, neuregulin, MAPK and AKT in invasive ductal carcinomas of the breast

  • H. Kaya1,*,
  • ˙I˙. Erbarut1
  • N. Özkan2
  • N. Bekirog˘lu3
  • S. S¸en4
  • U. Abacıg˘lu

1Department of Pathology, Turkey

2Department of Biostatistics, Turkey

3Department of Surgery, Turkey

4Department of Radiation Oncology, Marmara University Hospital, Istanbul, Turkey

DOI: 10.12892/ejgo200804350 Vol.29,Issue 4,July 2008 pp.350-356

Published: 10 July 2008

*Corresponding Author(s): H. Kaya E-mail: hkaya@superonline.com

Abstract

Background: The purpose of this study was to investigate the frequency of expression of the erbB/HER family of growth factor receptors, their ligand neuregulin alpha (NRG alpha) and the most important pathways activated by HER receptors that are mitogen-activated protein kinase (MAPK) and serine/threonine kinase (AKT) in invasive ductal carcinomas of the breast, not otherwise specified (IDC-NOS). Methods: 59 of the IDC-NOS of the breast were studied for ER, PR, EGFR, c-erbB-2, c-erbB-3, c-erbB-4, neuregulin Ab-3, phospho-AKT, and phospho-p44/42 map kinase using the streptavidin-biotin horseradish method. Results: Of the 59 tumours, 44 (75%) were ER+, 37 (63%) PR+, four (7%) EGFR+, seven (12%) c-erbB-2+, seven (12%) c-erbB-3+ and 14 (24%) c-erbB-4+alpha Strong cytoplasmic and/or nuclear immunoexpression was revealed in 17 (29%) cases for NRG alpha, 13 (22%) cases for p-AKT, and nuclear immunoexpression with p-MAPK was found in 17 (29%) cases. Conclusion: The results suggest that high-grade breast carcinomas are not only associated with ER/PR- negativity, but seem to be activated by receptor tyrosine kinase growth factors.

Keywords

Breast Carcinoma; HER family; Immunohistochemistry

Cite and Share

H. Kaya,˙I˙. Erbarut,N. Özkan,N. Bekirog˘lu,S. S¸en,U. Abacıg˘lu. Immunoexpression of HER family, neuregulin, MAPK and AKT in invasive ductal carcinomas of the breast. European Journal of Gynaecological Oncology. 2008. 29(4);350-356.

References

[1] Casalini P., Iorio M.V., Galmozzi E., Menard S.: “Role of HER receptors family in development and differentiation”. J. Cell. Physiol., 2004, 200, 343.

[2] Diermeier S., Horvath G., Knuechel-Clarke R., Hofstaedter F., Szollosi J., Brockhoff G.: “Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation”. Exp. Cell Res., 2005, 304, 604.

[3] Bacus S.S., Gudkov A.V., Esteva F.J., Yarden Y.: “Expression of erbB receptors and their ligands in breast cancer: implications to biological behavior and therapeutic response”. Breast Dis., 2000, 11, 63.

[4] Schechter A.L., Hung M.C., Vaidyanathan L., Weinberg R.A., Yang-Feng T.L., Francke U. et al.: “The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor”. Science, 1985, 6, 976.

[5] Dickson R.B., Lippman M.E.: “Growth factors in breast cancer”. Endocr. Rev., 1995, 16, 559.

[6] Yu D., Hung M.C.: “Overexpression of ErbB2 in cancer and ErbB2 targeting strategies”. Oncogene, 2000, 19, 6115.

[7] Elston C.W., Ellis I.O.: “Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up”. Histopathology, 1991, 19, 403.

[8] Wolff A.C., Hammond M.E., Schwartz J.N., Hagerty K.L., Allred D.C., Cote R.J. et al.: “American Society of Clinical Onco lo gy/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. American Society of Clinical Oncology; College of American Pathologists”. J. Clin. Oncol., 2007, 25, 118.

[9] Srinivasan R., Benton E., McCormick F., Thomas H., Gullick W.J.: “Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1α, neuregulin-1β, and betacellulin, in normal endometrium and endometrial cancer”. Clin. Cancer Res., 1999, 5, 2877.

[10] Carlomagno C., Perrone F., Gallo C., De Laurentiis M., Lauria R., Morabito A. 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., 1996, 14, 2702.

[11] Muss H.B., Thor A.D., Berry D.A., Kute T., Liu E.T., Koerner F. et al.: “c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer”. N. Engl. J. Med., 1994, 330, 1260.

[12] DiGiovanna M.P., Stern D.F., Edgerton S.M., Whalen S.G., Moore D. 2nd, Thor A.D.: “Relationship of epidermal growth factor receptor expression to ErbB-2 signaling activity and prognosis in breast cancer patients”. J. Clin. Oncol., 2005, 23, 1152.

[13] Bianchi S., Palli D., Falchetti M., Saieva C., Masala G., Mancini B. et al.: “ErbB-receptors expression and survival in breast carcinoma: a 15-year follow-up study”. J. Cell Physiol., 2006, 206, 702.

[14] Suo Z., Risberg B., Kalsson M.G., Willman K., Tierens A., Skovlund E. et al.: “EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival”. J. Pathol., 2002, 196, 17.

[15] Bucci B., D’Agnano I., Botti C., Mottolese M., Carico E., Zupi G. et al.: “EGF-R expression in ductal breast cancer: proliferation and prognostic implications”. Anticancer Res., 1997, 17, 769.

[16] Xue C., Wyckoff J., Liang F., Sidani M., Violini S., Tsai K.L. et al.: “Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis”. Cancer Res., 2006, 66, 192.

[17] Buchholz T.A., Tu X., Ang K.K., Esteva F.J., Kuerer H.M., Pusztai L. et al.: “Epidermal growth factor receptor expression correlates with poor survival in patients who have breast carcinoma treated with doxorubicin-based neoadjuvant chemotherapy”. Cancer, 2005, 104, 676.

[18] Rodriguez-Pinilla S.M., Rodriguez-Gil Y., Moreno-Bueno G., Sarrio D., Martin-Guijarro M.D., Hernandez L. et al.: “Sporadic invasive breast carcinomas with medullary features display a basal-like phenotype: an immunohistochemical and gene amplification study”. Am. J. Surg. Pathol., 2007, 31, 508.

[19] Beatty J.D., Atwood M., Tickman R., Reiner M.: “Metaplastic breast cancer: clinical significance”. Am. J. Surg., 2006, 191, 657.

[20] Grenier J., Soria J.C., Mathieu M.C., Andre F., Abdelmoula S., Velasco V. et al: “Differential immunohistochemical and biological profile of squamous cell carcinoma of the breast”. Anticancer Res., 2007, 27, 547.

[21] Rakha E.A., El-Sayed M.E., Green A.R., Lee A.H., Robertson J.F., Ellis I.O.: “Prognostic markers in triple negative breast cancer”. Cancer, 109, 2007, 25.

[22] Tovey S.M., Witton C.J., Bartlett J.M., Stanton P.D., Reeves J.R., Cooke T.G.: “Outcome and human epidermal growth factor receptor (HER) 1-4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling”. Breast Cancer Res., 2004, 6, 246.

[23] Barnes N.L., Khavari S., Boland G.P., Cramer A., Knox W.F., Bundred N.J.: “Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast”. Clin. Cancer Res., 2005, 11, 2163.

[24] Wiseman S.M., Makretsov N., Nielsen T.O., Gilks B., Yorida E., Cheang M. et al.: “Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival”. Cancer, 2005, 103, 1770.

[25] Holbro T., Beerli R.R., Maurer F., Koziczak M., Barbas C.F. 3rd, Hynes N.E.: “The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation”. Proc. Natl. Acad. Sci., 2003, 100, 8933.

[26] Travis A., Pinder S.E., Robertson J.F., Bell J.A., Wencyk P., Gullick W.J. et al.: “C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators”. Br. J. Cancer, 1996, 74, 229.

[27] Hudelist G., Singer C.F., Manavi M., Pischinger K., Kubista E., Czerwenka K. et al.: “Co-expression of ErbB-family members in human breast cancer: Her-2/neu is the preferred dimerization candidate in nodal-positive tumors”. Breast Cancer Res. Treatment, 2003, 80, 353.

[28] Tolgay Ocal I., Dolled-Filhart M., D’Aquila T.G., Camp R.L., Rimm D.L.: “Tissue microarray-based studies of patients with lymph node negative breast carcinoma show that met expression is associated with worse outcome but is not correlated with epidermal growth factor family receptors”. Cancer, 2003, 97, 1841.

[29] Raj E.H., Skinner A., Mahji U., Nirmala K.N., Ravichandran K., Shanta V. et al.: “Neuregulin 1-alpha expression in locally advanced breast cancer”. Breast, 2001, 10, 41.

[30] Diamonti A.J., Guy P.M., Ivanof C., Wong K., Sweeney C., Carraway K.L. 3rd: “An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels”. Proc. Natl. Acad. Sci., 2002, 99, 2866.

[31] Yen L., Cao Z., Wu X., Ingalla E.R., Baron C., Young L.J. et al.: “Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth”. Cancer Res., 2006, 66, 11279.

[32] Popnikolov N.K., Cavone S.M., Schultz P.M., Garcia F.U.: “Diagnostic utility of p75 neurotrophin receptor (p75NTR) as a marker of breast myoepithelial cells”. Mod. Pathol., 2005, 18, 1535.

[33] Reis-Filho J.S., Steele D., Di Palma S., Jones R.L., Savage K., James M. et al.: “Distribution and significance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue”. Mod. Pathol., 2006, 19, 307.

[34] Milde-Langosch K., Bamberger A.M., Rieck G., Grund D., Hemminger G., Muller V. et al: “Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer”. Br. J. Cancer, 2005, 20, 2206.

[35] Nakopoulou L., Mylona E., Rafailidis P., Alexandrou P., Giannopoulou I., Keramopoulos A.: “Effect of different ERK2 protein localizations on prognosis of patients with invasive breast carcinoma”. APMIS, 2005, 113, 693.

[36] Perez-Tenorio G., Stal O.: “Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients”. Br. J. Cancer, 2002, 86, 540.

[37] Zhou B.P., Hu M.C., Miller S.A., Yu Z., Xia W., Lin S.Y. et al.: “HER-2/neu blocks tumor necrosis factor induced apoptosis via the Akt/NF-kappaB pathway”. J. Biol. Chem., 2000, 275, 8027.

[38] Bose S., Chandran S., Mirocha J.M., Bose N.: “The Akt pathway in human breast cancer: a tissue-array-based analysis”. Mod. Pathol., 2006, 19, 238.

[39] Tokunaga E., Kimura Y., Mashino K., Oki E., Kataoka A., Ohno S., et al.: “Activation of PI3K/Akt signaling and hormone resistance in breast cancer”. Breast Cancer, 2006, 13, 137.

Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,500 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Biological Abstracts Easily discover critical journal coverage of the life sciences with Biological Abstracts, produced by the Web of Science Group, with topics ranging from botany to microbiology to pharmacology. Including BIOSIS indexing and MeSH terms, specialized indexing in Biological Abstracts helps you to discover more accurate, context-sensitive results.

Google Scholar Google Scholar is a freely accessible web search engine that indexes the full text or metadata of scholarly literature across an array of publishing formats and disciplines.

JournalSeek Genamics JournalSeek is the largest completely categorized database of freely available journal information available on the internet. The database presently contains 39226 titles. Journal information includes the description (aims and scope), journal abbreviation, journal homepage link, subject category and ISSN.

Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.

BIOSIS Previews BIOSIS Previews is an English-language, bibliographic database service, with abstracts and citation indexing. It is part of Clarivate Analytics Web of Science suite. BIOSIS Previews indexes data from 1926 to the present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Submission Turnaround Time

Conferences

Top