Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma

Br J Cancer. 2014 Aug 12;111(4):689-95. doi: 10.1038/bjc.2014.327. Epub 2014 Jun 17.


Background: Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas.

Methods: We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome.

Results: Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab.

Conclusions: Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Central Nervous System Neoplasms / drug therapy
  • Central Nervous System Neoplasms / enzymology*
  • Central Nervous System Neoplasms / mortality
  • Central Nervous System Neoplasms / secondary
  • Chemotherapy, Adjuvant
  • Class I Phosphatidylinositol 3-Kinases
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Middle Aged
  • Molecular Targeted Therapy
  • Phosphatidylinositol 3-Kinases / genetics
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction
  • Trastuzumab
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • src-Family Kinases
  • Trastuzumab