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KSR1 regulates BRCA1 degradation and inhibits breast cancer growth

J Stebbing1, H Zhang1, Y Xu1

  • 1Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial College Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, London, UK.

Oncogene
|June 10, 2014
PubMed

Insights

Kinase suppressor of Ras-1 (KSR1) acts as a tumor suppressor in breast cancer, unlike in other cancers. High KSR1 levels correlate with better patient survival and inhibited tumor growth, revealing a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Kinase suppressor of Ras-1 (KSR1) is implicated in Ras-dependent cancers, but its function in breast cancer remains largely uncharacterized.
  • Previous studies suggest KSR1's role in promoting tumorigenesis in various cancer types.

Purpose of the Study:

  • To investigate the role of KSR1 in breast cancer development and progression.
  • To elucidate the molecular mechanisms underlying KSR1's function in breast tumorigenesis.

Main Methods:

  • Analysis of clinical patient data (n>1000) and public datasets (Oncomine, microarray n=2878).
  • Genomic analysis of paired tumor and cell-free DNA.
  • In vitro cell culture assays (colony formation, 3D-matrigel, soft agar) and in vivo mouse xenograft models.
  • Western blotting and phospho-proteomic analysis to assess protein levels and signaling pathway activity.

Main Results:

  • High KSR1 expression is associated with improved disease-free and overall survival in breast cancer patients.
  • KSR1 overexpression inhibited colony formation, soft agar growth, and xenograft tumor growth in mice.
  • KSR1 functions as a tumor suppressor in a BRCA1-dependent manner, stabilizing BRCA1 protein by increasing BARD1 abundance and reducing BRCA1 ubiquitination.
  • No significant changes were observed in the canonical Ras-RAF-MAPK pathway upon KSR1 modulation.

Conclusions:

  • KSR1 acts as a tumor suppressor in breast cancer, contrary to its role in other malignancies.
  • KSR1's tumor-suppressive function is mediated through a novel mechanism involving the stabilization of BRCA1 protein via BARD1.
  • These findings establish KSR1 as a clinically relevant oncoprotein pathway modulator in breast cancer, offering potential therapeutic avenues.

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