Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer

Nat Med. 2011 Nov 20;17(12):1646-51. doi: 10.1038/nm.2580.

Abstract

Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Breast Neoplasms / genetics*
  • Carcinoma / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Fusion
  • Gene Rearrangement*
  • Humans
  • Mice
  • Mice, SCID
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Microtubules
  • Multigene Family
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism
  • Receptors, Notch / genetics*
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Transcriptome

Substances

  • Microtubule-Associated Proteins
  • NOTCH1 protein, human
  • NOTCH2 protein, human
  • Receptor, Notch1
  • Receptor, Notch2
  • Receptors, Notch
  • Protein-Serine-Threonine Kinases