Breast Cancer Research and Treatment

, Volume 149, Issue 1, pp 5–15 | Cite as

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

  • N. Elster
  • D. M. Collins
  • S. Toomey
  • J. Crown
  • A. J. Eustace
  • B. T. Hennessy


Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC.


Trastuzumab HER2 Breast cancer PI3 K 



This work was supported by the Irish Cancer Society (CRS11ELS), the Health Research Board (HRA/POR2012/054), RCSI Seed Funding 2014 and Molecular Therapeutics for Cancer Ireland (08-SRC-B1410).The authors have no financial disclosures.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • N. Elster
    • 1
  • D. M. Collins
    • 2
  • S. Toomey
    • 1
  • J. Crown
    • 2
    • 3
  • A. J. Eustace
    • 1
  • B. T. Hennessy
    • 1
    • 4
  1. 1.Department of Medical Oncology, Molecular Medicine Laboratories, ERC Smurift BuildingRoyal College of Surgeons in IrelandDublinIreland
  2. 2.National Institute for Cellular BiotechnologyDublin City UniversityDublinIreland
  3. 3.Department of Medical OncologySt Vincent’s University HospitalDublinIreland
  4. 4.Department of Medical OncologyBeaumont HospitalDublinIreland

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