Is Expression or Activation of Src Kinase Associated With Cancer-Specific Survival in ER-, PR- And HER2-negative Breast Cancer Patients?

Am J Pathol. 2009 Oct;175(4):1389-97. doi: 10.2353/ajpath.2009.090273. Epub 2009 Sep 17.

Abstract

The aim of the current study was to assess the expression levels of c-Src and phosphorylated Src kinase in human breast cancers and to establish if these are linked to oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status or patient survival. Tissue microarray technology was used to analyze 314 breast cancer specimens. Immunohistochemistry was performed using antibodies to c-Src, Y419Src, and Y215Src, and expression was assessed using the weighted histoscore method. High cytoplasmic c-Src kinase and high membrane phosphorylated activated Y419Src kinase was associated with decreased disease-specific survival. In contrast, phosphorylated activated nuclear and cytoplasmic Y215Src kinase expression levels were significantly associated with improved disease-specific survival. When the cohort was subdivided according to ER/PR/HER2 status, the ER-negative subgroup (105 patients) was associated with improved disease-specific survival and was found to be independent by multivariate analysis with a hazard ratio of 0.4 (interquartile range 0.2-0.8). High cytoplasmic c-Src expression was associated with decreased survival; high expression of activated c-Src (Y215) was associated with improved survival. This was potentiated in the ER/HER2-negative subgroup. Hence, administration of Src kinase inhibitors aiming to decrease phosphorylation should be approached with caution, especially in ER-negative patients. It is therefore essential to appropriately identify with the correct biomarkers which patients are most likely to respond to Src inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / enzymology*
  • Enzyme Activation
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Middle Aged
  • Models, Biological
  • Phosphotyrosine / metabolism
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism*
  • src-Family Kinases / metabolism*

Substances

  • Receptors, Estrogen
  • Receptors, Progesterone
  • Phosphotyrosine
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • src-Family Kinases