A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers.

Abstract

Background: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.

Methods: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.

Results: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.

Conclusion: Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.