ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness

Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited as BLBC malignancies rapidly develop resistant phenotypes. Using transcriptomic and proteomic approaches in human and murine BLBC cells, we aimed to elucidate the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in these mammary tumors. Specifically, we identified and characterized a novel short isoform of Roundabout Guidance Receptor 3 (ROBO3s), upregulated in BLBC in response to chemotherapy and encoding for a protein variant lacking the transmembrane domain. We established an important role for the ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving resistance of BLBC cells to cytotoxic drugs. By uncovering the conservation of ROBO3s expression across multiple cancer types, as well as its association with reduced BLBC-patient survival, we emphasize its potential as a prognostic marker and identify a novel attractive target for anti-cancer drug development.

Automated summary

This study reveals the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in basal-like breast cancer (BLBC) cells. The short isoform of Roundabout Guidance Receptor 3 (ROBO3s) was found to play an important role in mediating cancer stem cell properties and driving resistance of BLBC cells to cytotoxic drugs. The expression of ROBO3s is conserved across multiple cancer types and is associated with reduced survival in BLBC patients, highlighting its potential as a prognostic marker and a novel target for anti-cancer drug development.