Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers

Nat Commun. 2014 Aug 7;5:4577. doi: 10.1038/ncomms5577.

Abstract

Characterizing the genetic alterations leading to the more aggressive forms of oestrogen receptor-positive (ER+) breast cancers is of critical significance in breast cancer management. Here we identify recurrent rearrangements between the oestrogen receptor gene ESR1 and its neighbour CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal B tumours, through large-scale analyses of breast cancer transcriptome and copy number alterations. Further screening of 200 ER+ breast cancers identifies eight ESR1-CCDC170-positive tumours. These fusions encode amino-terminally truncated CCDC170 proteins (ΔCCDC170). When introduced into ER+ breast cancer cells, ΔCCDC170 leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity and enhanced xenograft tumour formation. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signalling and enhance cell motility. Together, this study identifies neoplastic ESR1-CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer.

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

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Breast Neoplasms / metabolism*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Separation
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Gene Rearrangement*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Ki-67 Antigen / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Open Reading Frames
  • Phenotype
  • RNA, Small Interfering / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • CCDC170 protein, human
  • Carrier Proteins
  • Estrogen Receptor alpha
  • GAB1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Ki-67 Antigen
  • RNA, Small Interfering
  • estrogen receptor alpha, human