Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7749-E7758. doi: 10.1073/pnas.1613859113. Epub 2016 Nov 14.

Abstract

Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1 Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

Keywords: Sleeping Beauty; TRPS1; breast cancer; metastasis; tumor suppressors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / secondary
  • Animals
  • Cell Line, Tumor
  • DNA Transposable Elements*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genes, Neoplasm
  • Genes, Tumor Suppressor
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / pathology
  • Mice, Transgenic
  • Mutagenesis
  • Mutation, Missense
  • PTEN Phosphohydrolase / genetics*
  • Proportional Hazards Models
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Repressor Proteins
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / pathology

Substances

  • DNA Transposable Elements
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-fos
  • Repressor Proteins
  • TRPS1 protein, human
  • Transcription Factors
  • fos-related antigen 1
  • PTEN Phosphohydrolase
  • Pten protein, mouse