Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 1/2008

Open Access 01-02-2008 | Research article

Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients

Authors: Andrea Sassen, Justine Rochon, Peter Wild, Arndt Hartmann, Ferdinand Hofstaedter, Stephan Schwarz, Gero Brockhoff

Published in: Breast Cancer Research | Issue 1/2008

Login to get access

Abstract

Introduction

The HER (human EGFR related) family of receptor tyrosine kinases (HER1/EGFR (epidermal growth factor receptor)/c-erbB1, HER2/c-erbB2, HER3/c-erbB3 and HER4/c-erbB4) shares a high degree of structural and functional homology. It constitutes a complex network, coupling various extracellular ligands to intracellular signal transduction pathways resulting in receptor interaction and cross-activation. The most famous family member is HER2, which is a target in Herceptin™ therapy in metastatic status and also in adjuvant therapy of breast cancer in the event of dysregulation as a result of gene amplification and resulting protein overexpression. The HER2-related HER receptors have been shown to interact directly with HER2 receptors and thereby mutually affect their activity and subsequent malignant growth potential. However, the clinical outcome with regard to total HER receptor state remains largely unknown.

Methods

We investigated HER1–HER4, at both the DNA and the protein level, using fluorescence in situ hybridisation (FISH) probes targeted to all four receptor loci and also immunohistochemistry in tissue microarrays derived from 278 breast cancer patients.

Results

We retrospectively found HER3 gene amplification with a univariate negative impact on disease-free survival (hazard ratio 2.35, 95% confidence interval 1.08 to 5.11, p = 0.031), whereas HER4 amplification showed a positive trend in overall and disease-free survival. Protein expression revealed no additional information.

Conclusion

Overall, the simultaneous quantification of HER3 and HER4 receptor genes by means of FISH might enable the rendering of a more precise stratification of breast cancer patients by providing additional prognostic information. The continuation of explorative and prospective studies on all HER receptors will be required for an evaluation of their potential use for specific therapeutic targeting with respect to individualised therapy.
Appendix
Available only for authorised users
Literature
1.
Menard S, Casalini P, Campiglio M, Pupa S, Agresti R, Tagliabue E: HER2 overexpression in various tumor types, focussing on its relationship to the development of invasive breast cancer. Ann Oncol. 2001, 12 (Suppl 1): S15-S19. 10.1023/A:1011151505425.CrossRefPubMed
2.
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989, 244: 707-712. 10.1126/science.2470152.CrossRefPubMed
3.
Tovey S, Dunne B, Witton CJ, Forsyth A, Cooke TG, Bartlett JM: Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?. Clin Cancer Res. 2005, 11: 4835-4842. 10.1158/1078-0432.CCR-05-0196.CrossRefPubMed
4.
Kirkegaard T, McGlynn LM, Campbell FM, Muller S, Tovey SM, Dunne B, Nielsen KV, Cooke TG, Bartlett JM: Amplified in breast cancer 1 in human epidermal growth factor receptor-positive tumors of tamoxifen-treated breast cancer patients. Clin Cancer Res. 2007, 13: 1405-1411. 10.1158/1078-0432.CCR-06-1933.CrossRefPubMed
5.
Graus-Porta D, Beerli RR, Daly JM, Hynes NE: ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997, 16: 1647-1655. 10.1093/emboj/16.7.1647.CrossRefPubMedPubMedCentral
6.
Holbro T, Civenni G, Hynes NE: The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003, 284: 99-110. 10.1016/S0014-4827(02)00099-X.CrossRefPubMed
7.
Yarden Y: The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001, 37 (Suppl 4): S3-S8. 10.1016/S0959-8049(01)00230-1.CrossRefPubMed
8.
Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006, 354: 2103-2111. 10.1056/NEJMoa054504.CrossRefPubMed
9.
Slamon D: Herceptin: increasing survival in metastatic breast cancer. Eur J Oncol Nurs. 2000, 4: 24-29. 10.1054/ejon.2000.0070.CrossRefPubMed
10.
Plosker GL, Keam SJ: Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer. Drugs. 2006, 66: 449-475. 10.2165/00003495-200666040-00005.CrossRefPubMed
11.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001, 344: 783-792. 10.1056/NEJM200103153441101.CrossRefPubMed
12.
13.
Normanno N, Di Maio M, De Maio E, De Luca A, de Matteis A, Giordano A, Perrone F: Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat Cancer. 2005, 12: 721-747. 10.1677/erc.1.00857.CrossRefPubMed
14.
Esteva FJ: Monoclonal antibodies, small molecules, and vaccines in the treatment of breast cancer. Oncologist. 2004, 9 (Suppl 3): 4-9. 10.1634/theoncologist.9-suppl_3-4.CrossRefPubMed
15.
Nahta R, Hortobagyi GN, Esteva FJ: Growth factor receptors in breast cancer: potential for therapeutic intervention. Oncologist. 2003, 8: 5-17. 10.1634/theoncologist.8-1-5.CrossRefPubMed
16.
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: 604-619. 10.1016/j.yexcr.2004.12.008.CrossRefPubMed
17.
Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell. 2000, 103: 211-225. 10.1016/S0092-8674(00)00114-8.CrossRefPubMed
18.
Tovey SM, Witton CJ, Bartlett JM, Stanton PD, Reeves JR, Cooke TG: 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: R246-R251. 10.1186/bcr783.CrossRefPubMedPubMedCentral
19.
Tsutsui S, Ohno S, Murakami S, Kataoka A, Kinoshita J, Hachitanda Y: Prognostic value of the combination of epidermal growth factor receptor and c-erbB-2 in breast cancer. Surgery. 2003, 133: 219-221. 10.1067/msy.2003.32.CrossRefPubMed
20.
Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM: Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer. J Pathol. 2003, 200: 290-297. 10.1002/path.1370.CrossRefPubMed
21.
de Azambuja E, Cardoso F, de Castro G, Colozza M, Mano MS, Durbecq V, Sotiriou C, Larsimont D, Piccart-Gebhart MJ, Paesmans M: Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer. 2007, 96: 1504-1513. 10.1038/sj.bjc.6603756.CrossRefPubMedPubMedCentral
22.
Traina A, Agostara B, Marasa L, Calabro M, Zarcone M, Carruba G: HER2/neu expression in relation to clinicopathologic features of breast cancer patients. Ann NY Acad Sci. 2006, 1089: 159-167. 10.1196/annals.1386.029.CrossRefPubMed
23.
Brockhoff G, Heckel B, Schmidt-Bruecken E, Plander M, Hofstaedter F, Vollmann A, Diermeier S: Differential impact of Cetuximab, Pertuzumab and Trastuzumab on BT474 and SK-BR-3 breast cancer cell proliferation. Cell Prolif. 2007, 40: 488-507. 10.1111/j.1365-2184.2007.00449.x.CrossRefPubMed
24.
Klopocki E, Kristiansen G, Wild PJ, Klaman I, Castanos-Velez E, Singer G, Stohr R, Simon R, Sauter G, Leibiger H, et al: Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors. Int J Oncol. 2004, 25: 641-649.PubMed
25.
Bubendorf L, Nocito A, Moch H, Sauter G: Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. J Pathol. 2001, 195: 72-79. 10.1002/path.893.CrossRefPubMed
26.
Contal C, O'Quigley J: An application of changepoint methods in studying the effect of age on survival in breast cancer. Comput Statist Data Anal. 1999, 30: 253-270. 10.1016/S0167-9473(98)00096-6.CrossRef
27.
Mandrekar JN, Mandrekar SJ, Cha SS: Cutpoint determination methods in survival analysis using SAS®. SAS Users Group 28, Seattle, Washington; March 30–April 2. 2003, 261-28.
28.
29.
Liberato NL, Marchetti M, Barosi G: Cost effectiveness of adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2007, 25: 625-633. 10.1200/JCO.2006.06.4220.CrossRefPubMed
30.
Kurian AW, Thompson RN, Gaw AF, Arai S, Ortiz R, Garber AM: A cost-effectiveness analysis of adjuvant trastuzumab regimens in early HER2/neu-positive breast cancer. J Clin Oncol. 2007, 25: 634-641. 10.1200/JCO.2006.06.3081.CrossRefPubMed
31.
Norum J, Olsen JA, Wist EA, Lonning PE: Trastuzumab in adjuvant breast cancer therapy. A model based cost-effectiveness analysis. Acta Oncol. 2007, 46: 153-164. 10.1080/02841860601096841.CrossRefPubMed
32.
Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001, 2: 127-137. 10.1038/35052073.CrossRefPubMed
33.
Pauletti G, Dandekar S, Rong H, Ramos L, Peng H, Seshadri R, Slamon DJ: Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol. 2000, 18: 3651-3664.CrossRefPubMed
34.
Lottner C, Schwarz S, Diermeier S, Hartmann A, Knuechel R, Hofstaedter F, Brockhoff G: Simultaneous detection of HER2/neu gene amplification and protein overexpression in paraffin-embedded breast cancer. J Pathol. 2005, 205: 577-584. 10.1002/path.1742.CrossRefPubMed
35.
Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE: The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA. 2003, 100: 8933-8938. 10.1073/pnas.1537685100.CrossRefPubMedPubMedCentral
36.
Neve RM, Sutterluty H, Pullen N, Lane HA, Daly JM, Krek W, Hynes NE: Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells. Oncogene. 2000, 19: 1647-1656. 10.1038/sj.onc.1203470.CrossRefPubMed
37.
Citri A, Skaria KB, Yarden Y: The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res. 2003, 284: 54-65. 10.1016/S0014-4827(02)00101-5.CrossRefPubMed
38.
Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A: Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J. 1995, 14: 4267-4275.PubMedPubMedCentral
39.
Liu B, Ordonez-Ercan D, Fan Z, Edgerton SM, Yang X, Thor AD: Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer. 2007, 120: 1874-1882. 10.1002/ijc.22423.CrossRefPubMed
40.
Jones RB, Gordus A, Krall JA, MacBeath G: A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature. 2006, 439: 168-174. 10.1038/nature04177.CrossRefPubMed
41.
Hudelist G, Singer CF, Manavi M, Pischinger K, Kubista E, Czerwenka K: 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 Treat. 2003, 80: 353-361. 10.1023/A:1024929522376.CrossRefPubMed
42.
Fuchs IB, Siemer I, Buhler H, Schmider A, Henrich W, Lichtenegger W, Schaller G, Kuemmel S: Epidermal growth factor receptor changes during breast cancer metastasis. Anticancer Res. 2006, 26: 4397-4401.PubMed
43.
Barnes NL, Khavari S, Boland GP, Cramer A, Knox WF, Bundred NJ: Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin Cancer Res. 2005, 11: 2163-2168. 10.1158/1078-0432.CCR-04-1633.CrossRefPubMed
44.
Suo Z, Risberg B, Kalsson MG, Willman K, Tierens A, Skovlund E, Nesland JM: EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival. J Pathol. 2002, 196: 17-25. 10.1002/path.1003.CrossRefPubMed
45.
Bacus SS, Chin D, Yarden Y, Zelnick CR, Stern DF: Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. Am J Pathol. 1996, 148: 549-558.PubMedPubMedCentral
46.
Vogt U, Bielawski K, Schlotter CM, Bosse U, Falkiewicz B, Podhajska AJ: Amplification of erbB-4 oncogene occurs less frequently than that of erbB-2 in primary human breast cancer. Gene. 1998, 223: 375-380. 10.1016/S0378-1119(98)00454-5.CrossRefPubMed
47.
Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, Harrelson J, Hynes N, Ethier S, Calvo B, et al: Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol. 2001, 21: 4265-4275. 10.1128/MCB.21.13.4265-4275.2001.CrossRefPubMedPubMedCentral
48.
Vidal GA, Clark DE, Marrero L, Jones FE: A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities. Oncogene. 2007, 26: 462-466. 10.1038/sj.onc.1209794.CrossRefPubMed
49.
Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE: The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res. 2006, 66: 6412-6420. 10.1158/0008-5472.CAN-05-2368.CrossRefPubMed
50.
Riese DJ, van Raaij TM, Plowman GD, Andrews GC, Stern DF: The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol. 1995, 15: 5770-5776.CrossRefPubMedPubMedCentral
51.
Suo Z, Emilsen E, Tveit KM, Nesland JM: Type 1 protein tyrosine kinases in benign and malignant breast lesions. Histopathology. 1998, 33: 514-521. 10.1046/j.1365-2559.1998.00498.x.CrossRefPubMed
52.
Feng SM, Sartor CI, Hunter D, Zhou H, Yang X, Caskey LS, Dy R, Muraoka-Cook RS, Earp HS: The HER4 cytoplasmic domain, but not its c-terminus, inhibits mammary cell proliferation. Mol Endocrinol. 2007, 21: 1861-1876. 10.1210/me.2006-0101.CrossRefPubMedPubMedCentral
53.
Ellis CM, Dyson MJ, Stephenson TJ, Maltby EL: HER2 amplification status in breast cancer: a comparison between immunohistochemical staining and fluorescence in situ hybridisation using manual and automated quantitative image analysis scoring techniques. J Clin Pathol. 2005, 58: 710-714. 10.1136/jcp.2004.023424.CrossRefPubMedPubMedCentral
54.
Stern DF: ErbBs in mammary development. Exp Cell Res. 2003, 284: 89-98. 10.1016/S0014-4827(02)00103-9.CrossRefPubMed
55.
Bieche I, Onody P, Tozlu S, Driouch K, Vidaud M, Lidereau R: Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer. 2003, 106: 758-765. 10.1002/ijc.11273.CrossRefPubMed
56.
Zaczek A, Welnicka-Jaskiewicz M, Bielawski KP, Jaskiewicz J, Badzio A, Olszewski W, Rhone P, Jassem J: Gene copy numbers of HER family in breast cancer. J Cancer Res Clin Oncol. 2008, 134: 271-279. 10.1007/s00432-007-0284-z.CrossRefPubMed
Metadata
Title
Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients
Authors
Andrea Sassen
Justine Rochon
Peter Wild
Arndt Hartmann
Ferdinand Hofstaedter
Stephan Schwarz
Gero Brockhoff
Publication date
01-02-2008
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2008
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr1843

Other articles of this Issue 1/2008

Breast Cancer Research 1/2008 Go to the issue

Research article

Chemopreventive effects of celecoxib are limited to hormonally responsive mammary carcinomas in the neu-induced retroviral rat model

Viewpoint

Re-evaluating early breast neoplasia

Commentary

Fatal attraction: why breast cancer cells home to bone

Review

Sugar and fat – that's where it's at: metabolic changes in tumors

Research article

Brca1 breast tumors contain distinct CD44+/CD24- and CD133+cells with cancer stem cell characteristics

Research article

Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits