title: Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma.
abstract: 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.
authors.affiliation: 1] Department of Pathology, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain [2] Research Unit, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Peiró
authors.affiliation: Research Unit, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Ortiz-Martínez
authors.affiliation: Department of Pathology, Clinica Girona, Joan Maragall 16, Girona 17003, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gallardo
authors.affiliation: Research Unit, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pérez-Balaguer
authors.affiliation: Department of Epidemiology, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Sánchez-Payá
authors.affiliation: Department of Clinical Oncology, University General Hospital of Alicante, Pintor Baeza 12, Alicante 03010, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Ponce
authors.affiliation: Department of Clinical Oncology, Hospital de la Santa Creu i Sant Pau, Sant Quintí 87-89, Barcelona 08041, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Tibau
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Sant Quintí 87-89, Barcelona 08041, Spain.
authors.forename: L
authors.initials: L
authors.lastname: López-Vilaro
authors.affiliation: Institut d'Investigacions Biomèdiques, Hospital de la Santa Creu i Sant Pau, Sant Quintí 87-89, Barcelona 08041, Spain Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Escuin
authors.affiliation: Department of Clinical Oncology, University General Hospital of Albacete, Hermanos Falcó s/n, Albacete 02006, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Adrover
authors.affiliation: Department of Clinical Oncology, Hospital de la Santa Creu i Sant Pau, Sant Quintí 87-89, Barcelona 08041, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Barnadas
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Sant Quintí 87-89, Barcelona 08041, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Lerma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D019061:src-Family Kinases; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human