Breast Cancer

, Volume 21, Issue 4, pp 472–481 | Cite as

Association of ErbB1–4 expression in invasive breast cancer with clinicopathological characteristics and prognosis

  • Saori Fujiwara
  • Mutsuko Ibusuki
  • Satoko Yamamoto
  • Yutaka Yamamoto
  • Hirotaka IwaseEmail author
Original Article



Human epidermal growth factor receptor type 2 (Her2)/ErbB2 plays a key role in the initiation and progression of invasive breast cancer. However, the prognostic relevance to breast cancer patients of the other ErbB family members has long been a matter of debate.


In a series of 250 primary invasive breast cancer patients, we performed a comprehensive analysis of ErbB1–4 at the levels of mRNA expression and gene copy number using real-time quantitative PCR. The relationship between the status of ErbB1–4 and the clinicopathological characteristics or prognosis was evaluated.


The mRNA expression of ErbB2, but not the other ErbB genes, was significantly correlated to copy number (P = 0.0005). ErbB3 and ErbB4 mRNA expression were positively correlated to each other (P < 0.0001). The mRNA expression of ErbB1/2 was inversely correlated to estrogen receptor (ER) and progesterone receptor (PgR) positivity, although mRNA expression of ErbB3/4 was positively correlated to ER and PgR positivity. Kaplan-Meier survival analysis showed that ErbB1 mRNA expression was associated with reduced survival. Neither ErbB2 nor ErbB3 mRNA expression had any association with survival, because half of the patients with Her2-positive tumors were treated with trastuzumab. High ErbB4 mRNA expression showed good prognosis with respect to breast cancer-specific survival


ErbB3 and ErbB4 mRNA expression, as well as well as that of ErbB1 and ErbB2, could be histopathological factors. ErbB3 mRNA was highly expressed in ER-positive tumors and has controversial prognostic value. ErbB4 mRNA expression was well correlated with ER positivity and good prognosis, indicating that ErbB4 may contribute to ER-dependent growth.


ErbB family Copy number mRNA expression Prognosis 



We thank Y. Azakami and Y. Sonoda for excellent technical support and A. Okabe for clinical data management.


  1. 1.
    Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26(45):6469–87.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Barros FF, Powe DG, Ellis IO, Green AR. Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatments. Histopathology. 2010;56(5):560–72.PubMedCrossRefGoogle Scholar
  3. 3.
    Rimawi MF, Shetty PB, Weiss HL, Schiff R, Osborne CK, Chamness GC, et al. Epidermal growth factor receptor expression in breast cancer association with biologic phenotype and clinical outcomes. Cancer. 2010;116(5):1234–42.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Ryden L, Jirstrom K, Haglund M, Stal O, Ferno M. Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up. Breast Cancer Res Treat. 2010;120(2):491–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Yamamoto Y, Ibusuki M, Nakano M, Kawasoe T, Hiki R, Iwase H. Clinical significance of basal-like subtype in triple-negative breast cancer. Breast Cancer. 2009;16(4):260–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Chiu CG, Masoudi H, Leung S, Voduc DK, Gilks B, Huntsman DG, et al. HER-3 overexpression is prognostic of reduced breast cancer survival: a study of 4046 patients. Ann Surg. 2010;251(6):1107–16.PubMedCrossRefGoogle Scholar
  7. 7.
    Koutras AK, Kalogeras KT, Dimopoulos MA, Wirtz RM, Dafni U, Briasoulis E, et al. Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Br J Cancer. 2008;99(11):1775–85.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, et al. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 2009;114(2):263–75.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Das PM, Thor AD, Edgerton SM, Barry SK, Chen DF, Jones FE. Reactivation of epigenetically silenced HER4/ERBB4 results in apoptosis of breast tumor cells. Oncogene. 2010;29(37):5214–9.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Sassen A, Rochon J, Wild P, Hartmann A, Hofstaedter F, Schwarz S, et al. Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Res. 2008;10(1):R2.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Yamamoto Y, Ibusuki M, Okumura Y, Kawasoe T, Kai K, Iyama K, et al. Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat. 2008;110(3):465–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Kristensen VN, Vaske CJ, Ursini-Siegel J, Van Loo P, Nordgard SH, Sachidanandam R, et al. Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling. Proc Natl Acad Sci USA. 2012;109(8):2802–7.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Nozoe T, Mori E, Iguchi T, Egashira A, Adachi E, Matsukuma A, et al. Immunohistochemical expression of epidermal growth factor receptor in breast cancer. Breast Cancer. 2011;18(1):37–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Badovinac-Crnjevic T, Jakic-Razumovic J, Podolski P, Plestina S, Sarcevic B, Munjas R, et al. Significance of epidermal growth factor receptor expression in breast cancer. Med Oncol. 2011;28(Suppl 1):S121–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Li QQ, Chen ZQ, Cao XX, Xu JD, Xu JW, Chen YY, et al. Involvement of NF-kappaB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial–mesenchymal transition of breast cancer cells. Cell Death Differ. 2011;18(1):16–25.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, et al. Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res. 2009;15(2):441–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Nemes S, Parris TZ, Danielsson A, Kannius-Janson M, Jonasson JM, Steineck G, et al. Segmented regression, a versatile tool to analyze mRNA levels in relation to DNA copy number aberrations. Genes Chromosomes Cancer. 2012;51(1):77–82.PubMedCrossRefGoogle Scholar
  18. 18.
    Sun Z, Asmann YW, Kalari KR, Bot B, Eckel-Passow JE, Baker TR, et al. Integrated analysis of gene expression, CpG island methylation, and gene copy number in breast cancer cells by deep sequencing. PLoS One. 2011;6(2):e17490.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Pawlowski V, Revillion F, Hebbar M, Hornez L, Peyrat JP. Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res. 2000;6(11):4217–25.PubMedGoogle Scholar
  20. 20.
    Sundvall M, Iljin K, Kilpinen S, Sara H, Kallioniemi OP, Elenius K. Role of ErbB4 in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13(2):259–68.PubMedCrossRefGoogle Scholar
  21. 21.
    Koutras AK, Fountzilas G, Kalogeras KT, Starakis I, Iconomou G, Kalofonos HP. The upgraded role of HER3 and HER4 receptors in breast cancer. Crit Rev Oncol Hematol. 2010;74(2):73–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68(14):5878–87.PubMedCrossRefGoogle Scholar
  23. 23.
    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(9):1874–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci USA. 2011;108(12):5021–6.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Rokicki J, Das PM, Giltnane JM, Wansbury O, Rimm DL, Howard BA, et al. The ERalpha coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium. Mol Cancer. 2010;9:150.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Zhu Y, Sullivan LL, Nair SS, Williams CC, Pandey AK, Marrero L, et al. Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. Cancer Res. 2006;66(16):7991–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Guler G, Iliopoulos D, Guler N, Himmetoglu C, Hayran M, Huebner K. Wwox and Ap2gamma expression levels predict tamoxifen response. Clin Cancer Res. 2007;13(20):6115–21.PubMedCrossRefGoogle Scholar
  28. 28.
    Naresh A, Thor AD, Edgerton SM, Torkko KC, Kumar R, Jones FE. The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis. Cancer Res. 2008;68(15):6387–95.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    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(3):462–6.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2012

Authors and Affiliations

  • Saori Fujiwara
    • 1
  • Mutsuko Ibusuki
    • 1
  • Satoko Yamamoto
    • 1
  • Yutaka Yamamoto
    • 1
  • Hirotaka Iwase
    • 1
    Email author
  1. 1.Department of Breast and Endocrine Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan

Personalised recommendations