Skip to main content

Advertisement

Log in

Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer

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

Abstract

HER2 receptor is overexpressed approximately in 20 % of human breast cancer (BC) and is a poor prognostic factor. Although therapies targeting this receptor have improved the prognosis of this cancer, up to 62 % patients treated with these drugs experiment progression during the first year of treatment. Some molecular mechanisms have been proposed to be responsible for this resistance, such as activation of alternative signaling pathways (through ERBB receptors and non-ERBB receptors or increased expression of ligands and alterations in HER2 signaling components). In this article, we will review the influence of genetic markers in non-HER2 signaling pathways investigated to date as cause of resistance to HER2-targeted drugs in HER2-positive BC patients. GRB7, included in the 17q12 amplicon, has been associated to poor prognosis in BC patients. Biomarkers like EPHAR and SRC, have demonstrated clinical relevance and prognostic value in HER2-positive BC patients. Non-invasive biomarkers, such as elevated IGF1 serum levels have been revealed as interesting biomarkers to be considered as predictors of trastuzumab clinical outcomes in BC patients. However, the prognostic value of most of the biomarkers investigated to date, such as HER3, IGF1R, PIK3CA, or AKT1 cannot be fully established yet, since results have not been conclusive.

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

Fig. 1

Similar content being viewed by others

Abbreviations

BC:

Breast cancer

CBR:

Clinical benefit rate

CR:

Complete response

ER:

Estrogen receptor

LABC:

Locally advance breast cancer

MBC:

Metastatic breast cancer

hR:

Hormonal receptor

NS:

Non-significant

pCR:

Pathologic complete response

PFS:

Progression-free survival

RFS:

Relapse-free survival

RR:

Response rate

OR:

Odds ratio

ORR:

Overall response rate

OS:

Overall survival

TFR:

Trastuzumab failure rate

TTP:

Time to progression

References

  1. WHO. OMS | Cáncer de mama: prevención y control. WHO

  2. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  PubMed  Google Scholar 

  3. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137

    Article  CAS  PubMed  Google Scholar 

  4. Carter P, Presta L, Gorman CM et al (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89(10):4285–4289

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Nahta R, Hung M-C, Esteva FJ (2004) The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 64(7):2343–2346

    Article  CAS  PubMed  Google Scholar 

  6. Lewis Phillips GD, Li G, Dugger DL et al (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68(22):9280–9290

    Article  CAS  PubMed  Google Scholar 

  7. Xia W, Mullin RJ, Keith BR et al (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21(41):6255–6263

    Article  CAS  PubMed  Google Scholar 

  8. Cobleigh MA, Vogel CL, Tripathy D et al (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17(9):2639–2648

    CAS  PubMed  Google Scholar 

  9. Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743

    Article  CAS  PubMed  Google Scholar 

  10. Verma S, Miles D, Gianni L et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367(19):1783–1791

    Article  CAS  PubMed  Google Scholar 

  11. Swain SM, Kim S-B, Cortés J et al (2013) Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14(6):461–471

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792

    Article  CAS  PubMed  Google Scholar 

  13. Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S (2011) Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials. Anticancer Drugs 22(2):128–135

    Article  CAS  PubMed  Google Scholar 

  14. Robinson AG, Turbin D, Thomson T et al (2006) Molecular predictive factors in patients receiving trastuzumab-based chemotherapy for metastatic disease. CLBC 7(3):254–261

    CAS  Google Scholar 

  15. Wang SE, Xiang B, Guix M et al (2008) Transforming growth factor beta engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab. Mol Cell Biol 28(18):5605–5620

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Straussman R, Morikawa T, Shee K et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Wheeler DL, Iida M, Dunn EF (2009) The role of Src in solid tumors. Oncologist 14(7):667–678

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Earp HS, Dawson TL, Li X, Yu H (1995) Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat 35(1):115–132

    Article  CAS  PubMed  Google Scholar 

  19. Wang K, Yamamoto H, Chin JR, Werb Z, Vu TH (2004) Epidermal growth factor receptor-deficient mice have delayed primary endochondral ossification because of defective osteoclast recruitment. J Biol Chem 279(51):53848–53856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Spivak-Kroizman T, Rotin D, Pinchasi D, Ullrich A, Schlessinger J, Lax I (1992) Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. J Biol Chem 267(12):8056–8063

    CAS  PubMed  Google Scholar 

  21. Boulbes DR, Arold ST, Chauhan GB et al (2014) HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer. Mol Oncol 9:586–600

    Article  PubMed  Google Scholar 

  22. Lee HJ, Seo AN, Kim EJ et al (2015) Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer. Br J Cancer 112(1):103–111

    Article  CAS  PubMed  Google Scholar 

  23. Gonzalez-Angulo AM, Hennessy BT, Meric-Bernstam F et al (2011) Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer. Clin Proteomics 8(1):11

    Article  PubMed Central  PubMed  Google Scholar 

  24. Henjes F, Bender C, von der Heyde S et al (2012) Strong EGFR signaling in cell line models of ERBB2-amplified breast cancer attenuates response towards ERBB2-targeting drugs. Oncogenesis 1:e16

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Cheng H, Ballman K, Vassilakopoulou M et al (2014) EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial. Br J Cancer 111(6):1065–1071

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Gallardo A, Lerma E, Escuin D et al (2012) Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer 106(8):1367–1373

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Fabi A, Merola R, Ferretti G et al (2013) Epidermal growth factor receptor gene copy number may predict lapatinib sensitivity in HER2-positive metastatic breast cancer. Expert Opin Pharmacother 14(6):699–706

    Article  CAS  PubMed  Google Scholar 

  28. Network Cancer Genome Atlas (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70

    Article  Google Scholar 

  29. Lee-Hoeflich ST, Crocker L, Yao E et al (2008) A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 68(14):5878–5887

    Article  CAS  PubMed  Google Scholar 

  30. Jaiswal BS, Kljavin NM, Stawiski EW et al (2013) Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23(5):603–617

    Article  CAS  PubMed  Google Scholar 

  31. Junttila TT, Akita RW, Parsons K et al (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15(5):429–440

    Article  CAS  PubMed  Google Scholar 

  32. Kurebayashi J, Kanomata N, Yamashita T et al (2013) Prognostic value of phosphorylated HER2 in HER2-positive breast cancer patients treated with adjuvant trastuzumab. Breast Cancer 22:292–299

    Article  PubMed  Google Scholar 

  33. Han S-W, Cha Y, Paquet A et al (2012) Correlation of HER2, p95HER2 and HER3 expression and treatment outcome of lapatinib plus capecitabine in her2-positive metastatic breast cancer. PLoS ONE 7(7):e39943

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Cha Y, Han S-W, Seol H et al (2014) Immunohistochemical features associated with sensitivity to lapatinib-plus-capecitabine and resistance to trastuzumab in HER2-positive breast cancer. Anticancer Res 34(8):4275–4280

    PubMed  Google Scholar 

  35. Lipton A, Goodman L, Leitzel K et al (2013) HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat 141(1):43–53

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Bae SY, La Choi Y, Kim S et al (2013) HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients. Breast Cancer Res Treat 139(3):741–750

    Article  CAS  PubMed  Google Scholar 

  37. Baselga J, Cortes J, Im SA et al (2014) Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol 32(33):3753–3761

    Article  CAS  PubMed  Google Scholar 

  38. Portier BP, Minca EC, Wang Z et al (2013) HER4 expression status correlates with improved outcome in both neoadjuvant and adjuvant Trastuzumab treated invasive breast carcinoma. Oncotarget 4(10):1662–1672

    Article  PubMed Central  PubMed  Google Scholar 

  39. Sassen A, Diermeier-Daucher S, Sieben M et al (2009) Presence of HER4 associates with increased sensitivity to Herceptin in patients with metastatic breast cancer. Breast Cancer Res 11(4):R50

    Article  PubMed Central  PubMed  Google Scholar 

  40. Nafi S, Generali D, Kramer-Marek G et al (2014) Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer. Oncotarget 5:5934

    PubMed Central  Google Scholar 

  41. Nahta R, Yuan LXH, Zhang B, Kobayashi R, Esteva FJ (2005) Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 65(23):11118–11128

    Article  CAS  PubMed  Google Scholar 

  42. Shattuck DL, Miller JK, Carraway KL, Sweeney C (2008) Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 68(5):1471–1477

    Article  CAS  PubMed  Google Scholar 

  43. Vaught D, Brantley-Sieders DM, Chen J (2008) Eph receptors in breast cancer: roles in tumor promotion and tumor suppression. Breast Cancer Res 10(6):217

    Article  PubMed Central  PubMed  Google Scholar 

  44. Liang K, Esteva FJ, Albarracin C et al (2010) Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell 18(5):423–435

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Grant ES, Ross MB, Ballard S, Naylor A, Habib FK (1998) The insulin-like growth factor type I receptor stimulates growth and suppresses apoptosis in prostatic stromal cells. J Clin Endocrinol Metab 83(9):3252–3257

    Article  CAS  PubMed  Google Scholar 

  46. Werner H, Karnieli E, Rauscher FJ, LeRoith D (1996) Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA 93(16):8318–8323

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Gianni L, Bianchini G, Kiermaier A, Bianchi G, Im Y-H, Pienkowski T, Roman L, Liu M-C, Tseng L-M, Ratnayake J, Szado T, Ross GA, Valagussa P (2012) S5-1: Neoadjuvant pertuzumab (P) and trastuzumab (H): biomarker analyses of a 4-arm randomized phase II study (NeoSphere) in patients (pts) with HER2-positive breast cancer (BC). Cancer Res 71:S5-1. doi:10.1158/0008-5472.SABCS11-S5-1

  48. Reinholz MM, Dueck AC, Chen B (2011) Effect of IGF1R protein expression on benefit to adjuvant trastuzumab in early-stage HER2 + breast cancer in NCCTG N9831 trial. [Internet]. meetinglibrary.asco.org. 29, Abstr 10503. Available from: http://meetinglibrary.asco.org/content/81832-102

  49. Gianni L, Pienkowski T, Im Y-H et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13(1):25–32

    Article  CAS  PubMed  Google Scholar 

  50. Ferry RJ, Cerri RW, Cohen P (1999) Insulin-like growth factor binding proteins: new proteins, new functions. Horm Res 51(2):53–67

    Article  CAS  PubMed  Google Scholar 

  51. Tas F, Karabulut S, Bilgin E, Tastekin D, Duranyildiz D 2014) Clinical significance of serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in patients with breast cancer. Tumour Biol [Internet] 35(9):9303–9309. Available from: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24943688&retmode=ref&cmd=prlinks

  52. Hartog H, Boezen HM, de Jong MM, Schaapveld M, Wesseling J, van der Graaf WTA (2013) Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer. Breast 22(6):1155–1160

    Article  CAS  PubMed  Google Scholar 

  53. Dean M, Park M, Le Beau MM et al (1985) The human met oncogene is related to the tyrosine kinase oncogenes. Nature 318(6):385–388

    Article  CAS  PubMed  Google Scholar 

  54. Bottaro DP, Rubin JS, Faletto DL et al (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251(4995):802–804

    Article  CAS  PubMed  Google Scholar 

  55. Minuti G, Cappuzzo F, Duchnowska R et al (2012) Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer. Br J Cancer 107(5):793–799

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Koh YW, Lee HJ, Ahn J-H, Lee JW, Gong G (2014) MET expression is associated with disease-specific survival in breast cancer patients in the neoadjuvant setting. Pathol Res Pract 210(8):494–500

    Article  CAS  PubMed  Google Scholar 

  57. Muendlein A, Hubalek M, Geller-Rhomberg S et al (2014) Significant survival impact of MACC1 polymorphisms in HER2 positive breast cancer patients. Eur J Cancer 50(12):2134–2141

    Article  CAS  PubMed  Google Scholar 

  58. Zhuang G, Brantley-Sieders DM, Vaught D et al (2010) Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res 70(1):299–308

    Article  CAS  PubMed  Google Scholar 

  59. Damen JE, Mui AL, Puil L, Pawson T, Krystal G (1993) Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor. Blood 81(12):3204–3210

    CAS  PubMed  Google Scholar 

  60. Massagué J (2008) TGFbeta in Cancer. Cell 134(2):215–230

    Article  PubMed Central  PubMed  Google Scholar 

  61. Wilson IA, Jolliffe LK (1999) The structure, organization, activation and plasticity of the erythropoietin receptor. Curr Opin Struct Biol 9(6):696–704

    Article  CAS  PubMed  Google Scholar 

  62. Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF (1993) Structure, function, and activation of the erythropoietin receptor. Blood 81(9):2223–2236

    CAS  PubMed  Google Scholar 

  63. Zhang C, Duan X, Xu L, Ye J, Zhao J, Liu Y (2012) Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells. Breast Cancer Res Treat 136(3):739–748

    Article  CAS  PubMed  Google Scholar 

  64. Flanagan JG, Gale NW, Hunter T, Pasquale EB, Tessier-Lavigne M (1997) Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee Cell 90(3):403–404

    CAS  Google Scholar 

  65. Brantley-Sieders DM, Jiang A, Sarma K et al (2011) Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS ONE 6(9):e24426

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29(2):117–129

    Article  CAS  PubMed  Google Scholar 

  67. Ewan KB, Shyamala G, Ravani SA et al (2002) Latent transforming growth factor-beta activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation. Am J Pathol 160(6):2081–2093

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Garratt AN (2006) “To erb-B or not to erb-B…” Neuregulin-1/ErbB signaling in heart development and function. J Mol Cell Cardiol 41(2):215–218

    Article  CAS  PubMed  Google Scholar 

  69. Tan W, Wang Y, Gold B et al (2007) Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. J Biol Chem 282(33):24343–24351

    Article  CAS  PubMed  Google Scholar 

  70. Meyer D, Yamaai T, Garratt A et al (1997) Isoform-specific expression and function of neuregulin. Development 124(18):3575–3586

    CAS  PubMed  Google Scholar 

  71. Smith BL, Chin D, Maltzman W, Crosby K, Hortobagyi GN, Bacus SS (2004) The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins. Br J Cancer 91(6):1190–1194

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Dunn M, Sinha P, Campbell R et al (2004) Co-expression of neuregulins 1, 2, 3 and 4 in human breast cancer. J Pathol 203(2):672–680

    Article  CAS  PubMed  Google Scholar 

  73. Cheng L, Zha Z, Lang B, Liu J, Yao X (2009) Heregulin-beta1 promotes metastasis of breast cancer cell line SKBR3 through upregulation of Snail and induction of epithelial-mesenchymal transition. Cancer Lett 280(1):50–60

    Article  CAS  PubMed  Google Scholar 

  74. Xia W, Petricoin EF, Zhao S et al (2013) An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res 15(5):R85

    Article  PubMed Central  PubMed  Google Scholar 

  75. McInnes C, Wang J, Moustafa Al AE, Yansouni C, O’Connor-McCourt M, Sykes BD (1998) Structure-based minimization of transforming growth factor-alpha (TGF-alpha) through NMR analysis of the receptor-bound ligand. Design, solution structure, and activity of TGF-alpha 8-50. J Biol Chem 273(42):27357–27363

    Article  CAS  PubMed  Google Scholar 

  76. Rhee J, Han S-W, Cha Y et al (2011) High serum TGF-α predicts poor response to lapatinib and capecitabine in HER2-positive breast cancer. Breast Cancer Res Treat 125(1):107–114

    Article  CAS  PubMed  Google Scholar 

  77. Cooper JA, Gould KL, Cartwright CA, Hunter T (1986) Tyr527 is phosphorylated in pp60c-src: implications for regulation. Science 231(4744):1431–1434

    Article  CAS  PubMed  Google Scholar 

  78. Roskoski R (2005) Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun 331(1):1–14

    Article  CAS  PubMed  Google Scholar 

  79. Zhang S, Huang W-C, Li P et al (2011) Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med [Internet] 17(4):461–469. Available from: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=21399647&retmode=ref&cmd=prlinks

  80. Peiró G, Ortiz-Martínez F, Gallardo A et al (2014) Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma. Br J Cancer 111(4):689–695

    Article  PubMed Central  PubMed  Google Scholar 

  81. Marchini C, Gabrielli F, Iezzi M et al (2011) The human splice variant Δ16HER2 induces rapid tumor onset in a reporter transgenic mouse. PLoS ONE 6(4):e18727

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Castagnoli L, Iezzi M, Ghedini GC et al (2014) Activated d16HER2 homodimers and Src kinase mediate optimal efficacy for trastuzumab. Cancer Res 74(21):6248–6259

    Article  CAS  PubMed  Google Scholar 

  83. Stein D, Wu J, Fuqua SA et al (1994) The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. EMBO J 13(6):1331–1340

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Margolis B, Silvennoinen O, Comoglio F et al (1992) Higher-efficiency expression/cloning of epidermal growth factor-receptor- binding proteins with Src homology 2 domains. Proc Natl Acad Sci USA 89(1):8894–8898

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Chu P-Y, Huang L-Y, Hsu C-H et al (2009) Tyrosine phosphorylation of growth factor receptor-bound protein-7 by focal adhesion kinase in the regulation of cell migration, proliferation, and tumorigenesis. J Biol Chem 284(30):20215–20226

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Fiddes RJ, Campbell DH, Janes PW et al (1998) Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3. J Biol Chem 273(13):7717–7724

    Article  CAS  PubMed  Google Scholar 

  87. Nadler Y, González AM, Camp RL, Rimm DL, Kluger HM, Kluger Y (2010) Growth factor receptor-bound protein-7 (Grb7) as a prognostic marker and therapeutic target in breast cancer. Ann Oncol 21(3):466–473

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Ramsey B, Bai T, Hanlon Newell A et al (2011) GRB7 protein over-expression and clinical outcome in breast cancer. Breast Cancer Res Treat 127(3):659–669

    Article  CAS  PubMed  Google Scholar 

  89. Montemurro F, Prat A, Rossi V et al (2014) Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer. Mol Oncol. 8(1):20–26

    Article  CAS  PubMed  Google Scholar 

  90. Glynn RW, Miller N, Mahon S, Kerin MJ (2012) Expression levels of HER2/neu and those of collocated genes at 17q12-21, in breast cancer. Oncol Rep 28(1):365–369

    PubMed  Google Scholar 

  91. Lacle MM, Moelans CB, Kornegoor R et al (2015) Chromosome 17 copy number changes in male breast cancer. Cell Oncol (Dordr). 38(3):237–245

    Article  PubMed Central  PubMed  Google Scholar 

  92. Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413

    Article  CAS  PubMed  Google Scholar 

  93. Qiao J-H, Jiao D-C, Lu Z-D, Yang S, Liu Z-Z (2015) Clinical significance of topoisomerase 2A expression and gene change in operable invasive breast cancer. Tumour Biol

  94. Fountzilas G, Dafni U, Bobos M et al (2013) Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials. BMC Cancer 13(1):163

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Jones SE, Collea R, Paul D et al (2013) Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol 14(11):1121–1128

    Article  CAS  PubMed  Google Scholar 

  96. Liu R, Lv Q-L, Yu J et al (2015) Correlating transcriptional networks with pathological complete response following neoadjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 151(3):607–618

    Article  CAS  PubMed  Google Scholar 

  97. Prempree T, Wongpaksa C (2006) Mutations of HER2 gene in HER2-positive metastatic breast cancer. ASCO Meeting Abstracts 24(18_suppl): 13118

  98. Grob T, Sandmann M, Quaas A, Marx A, Sauter G (2014) Concomitant mutation and amplification of the ERBB2 (HER2) gene in human tumors. [Internet]. J Clin Oncol 32(5s), suppl-abstr 11071. Available from: http://meetinglibrary.asco.org/content/133558-144

  99. Arteaga CL, Engelman JA (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25(3):282–303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Madrid Paredes A, Cañadas-Garre M, Sánchez-Pozo A, Calleja-Hernández MÁ (2015) De novo resistance biomarkers to anti-HER2 therapies in HER2-positive breast cancer. Pharmacogenomics 1–16

  101. Brunetto E, Ferrara AM, Rampoldi F et al (2013) CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: implication for a potential clinical relevance in trastuzumab treatment. Neoplasia 15(6):579–590

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Tanioka M, Sakai K, Sudo T et al (2014) Transcriptional CCND1 expression as a predictor of poor response to neoadjuvant chemotherapy with trastuzumab in HER2-positive/ER-positive breast cancer. Breast Cancer Res Treat 147:513–525

    Article  CAS  PubMed  Google Scholar 

  103. Pandey JP, Namboodiri AM, Kistner-Griffin E et al (2013) Racially restricted contribution of immunoglobulin Fcγ and Fcγ receptor genotypes to humoral immunity to human epidermal growth factor receptor 2 in breast cancer. Clin Exp Immunol 171(3):273–277

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Pandey JP, Kistner-Griffin E, Black L et al (2014) IGKC and FcγR genotypes and humoral immunity to HER2 in breast cancer. Immunobiology 219(2):113–117

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The results of this investigation are part of the doctoral thesis presented by Adela Madrid-Paredes at the University of Granada.

Funding

This work was partly supported by a contract for Marisa Cañadas-Garre (Técnicos de Apoyo Subprogram. CA12/00097) from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marisa Cañadas-Garre.

Ethics declarations

Conflict of Interest

The authors declare that there is not conflict of interest that could be perceived as prejudicing the impartiality of the research reported and there is not any competing financial interest in relation to the work described in this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Madrid-Paredes, A., Cañadas-Garre, M., Sánchez-Pozo, A. et al. Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer. Breast Cancer Res Treat 153, 493–505 (2015). https://doi.org/10.1007/s10549-015-3578-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-015-3578-x

Keywords

Navigation