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.

Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

“…Similar results have been previously obtained in other cancer types, particularly in breast, colon, and hepatocellular carcinomas (25)(26)(27).…”

Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells

“…This observation is consistent with the negligible efficacy of SFK inhibitors in patients with advanced metastatic disease (27). In fact, elevated Src activity is associated with decreased disease-free survival, increased relapse, and lower recurrence-free survival in patients with triple-negative and estrogen receptor-positive BC, underscoring the potential importance of targeting Src (28)(29)(30). However, clinical trials with AZD0530 and other dual SFK/ABL inhibitors have shown very modest efficacy in treating advanced triple-negative BCs (31), suggesting that these regimens may miss a "window of opportunity" as the metastatic proliferative switch occurs.…”

Dasatinib as a Single Agent in Triple-Negative Breast Cancer: Results of an Open-Label Phase 2 Study

“…A recent study found that subcellular SRC localization and the site of SRC phosphorylation were associated with different breast cancer survival outcomes. Tumors with high cytoplasmic SRC levels or membrane-associated tyrosine-419 phosphorylated SRC were associated with decreased survival, whereas those with activated nuclear and cytoplasmic tyrosine-215 phosphorylated SRC had a significantly improved survival benefit (26). Preclinical evidence suggests that, as a result of complex crosstalk between SRC-regulated signaling pathways, SRC inhibition may result in a paradoxical increase in proliferative signaling in breast cancer cells (27).…”