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ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness

Marcel Werner1,2, Anna Dyas1,3,4, Iwan Parfentev5

  • 1Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.

Cell Death & Disease
|September 3, 2022
PubMed

Insights

A novel Roundabout Guidance Receptor 3 short isoform (ROBO3s) drives aggressive basal-like breast cancer (BLBC) and chemotherapy resistance by activating the Hippo-YAP pathway. ROBO3s is a potential prognostic marker and therapeutic target for BLBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Basal-like breast cancer (BLBC) is aggressive with poor prognosis.
  • Limited targeted therapies necessitate chemotherapy, but resistance is common.
  • Understanding resistance mechanisms is crucial for BLBC treatment.

Purpose of the Study:

  • To identify molecular mechanisms of aggressive and chemotherapy-resistant phenotypes in BLBC.
  • To characterize a novel Roundabout Guidance Receptor 3 short isoform (ROBO3s).
  • To investigate the role of ROBO3s in BLBC chemoresistance and cancer stem cell properties.

Main Methods:

  • Transcriptomic and proteomic analyses in human and murine BLBC cells.
  • Identification and characterization of the ROBO3s isoform.
  • Investigation of ROBO3s function in mediating cancer stem cell properties and Hippo-YAP pathway activation.
  • Analysis of ROBO3s expression across cancer types and its association with patient survival.

Main Results:

  • A novel, short isoform of Roundabout Guidance Receptor 3 (ROBO3s) was identified, lacking a transmembrane domain.
  • ROBO3s is upregulated in BLBC, particularly in response to chemotherapy.
  • ROBO3s promotes cancer stem cell properties and stimulates the Hippo-YAP signaling pathway.
  • ROBO3s expression is conserved across cancer types and correlates with reduced BLBC patient survival.

Conclusions:

  • The ROBO3s isoform plays a critical role in driving BLBC aggressiveness and chemotherapy resistance.
  • ROBO3s mediates these effects by activating the Hippo-YAP signaling pathway.
  • ROBO3s represents a promising prognostic marker and a novel therapeutic target for BLBC treatment.

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