ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness.


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Authors
Dyas, Anna 
Parfentev, Iwan 
Schmidt, Geske E 
Abstract

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.

Description
Keywords
Article, /631/67/1347, /631/67/71, /631/67/395, /631/67/1857, /13/100, /38/91, /42/89, /82/58, /96/106, /64/60, article
Journal Title
Cell Death Dis
Conference Name
Journal ISSN
2041-4889
2041-4889
Volume Title
Publisher
Springer Science and Business Media LLC
Sponsorship
Erich und Gertrud Roggenbuck-Stiftung (Erich and Gertrud Roggenbuck Foundation) (Unravelling epigenetic mechanisms of CAF-chemotherapy resistance in mammary carcinoma)