Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signaling

Abstract

BACKGROUND: HER2 overexpression leads to aggressive mammary tumor growth. Although the prognosis of HER2+ tumors in humans is greatly improved using biologicals, therapy resistance, which may be caused by increased PI3K, cSRC or Wnt activity, is a major concern. A recent analysis of 12 canine mammary cell lines showed an association between HER2/3 overexpression and PTEN deletion with elevated Wnt-signaling. Wnt-activity appeared to be insensitive to PI3K inhibitors but sensitive to Src-I1. We hypothesized that Wnt activation, was caused by HER2/3-activated cSRC activation. METHODS: The role of HER2/3 on Wnt signaling was investigated by silencing HER2/3 expression using specific siRNAs. Next, the effect of an EGFR/HER2 tyrosine kinase inhibitor on Wnt activity and migration was investigated and compared to other TKIs of related signaling pathways. Finally, two TKIs, a cSRC and a PI3K inhibitor, were investigated in a zebrafish xenograft model. RESULTS: Silencing of HER1-3 did not inhibit the intrinsic high Wnt activity, whereas the HER kinase inhibitor afatinib showed enhanced Wnt activity. The strongest inhibition of Wnt activity and cell viability and migration was shown by cSRC inhibitors, which also showed strong inhibition of cell viability and metastasis in a zebrafish xenograft model. CONCLUSION: HER2/3 overexpression or HER2/3-induced cSRC activation is not the cause of enhanced Wnt activity. However, inhibition of cSRC resulted in a strong inhibition of Wnt activity and cell migration and metastasis. Further studies are needed to unravel the mechanism of cSRC activation and cSRC inhibition to restore sensitivity to HER-inhibitors in HER2/3-positive breast cancer. This article is protected by copyright. All rights reserved.