title: Is expression or activation of Src kinase associated with cancer-specific survival in ER-, PR- and HER2-negative breast cancer patients?
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.
authors.affiliation: Section of Surgery, Division of Cancer Sciences and Molecular Pathology, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Elsberger
authors.forename: Bingchao A
authors.initials: BA
authors.lastname: Tan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Sylvia B F
authors.initials: SB
authors.lastname: Brown
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mallon
authors.forename: Sian M
authors.initials: SM
authors.lastname: Tovey
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cooke
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D008954:Models, Biological; D019000:Phosphotyrosine / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019000:Phosphotyrosine; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019061:src-Family Kinases; C508053:ERBB2 protein, human