The interplay between TEAD4 and KLF5 promotes breast cancer partially through inhibiting the transcription of p27Kip1

Oncotarget. 2015 Jul 10;6(19):17685-97. doi: 10.18632/oncotarget.3779.

Abstract

Growing evidence suggests that YAP/TAZ are mediators of the Hippo pathway and promote breast cancer. However, the roles of YAP/TAZ transcription factor partners TEADs in breast cancer remain unclear. Here we found that TEAD4 was expressed in breast cancer cell lines, especially in triple negative breast cancers (TNBC) cell lines. TEAD4 binds to KLF5. Knockdown of either TEAD4 or KLF5 in HCC1937 and HCC1806 cells induced the expression of CDK inhibitor p27. Depletion of either TEAD4 or KLF5 activated the p27 gene promoter and increased the p27 mRNA levels. Depletion of p27 partially prevents growth inhibition caused by TEAD4 and KLF5 knockdown. TEAD4 overexpression stimulated proliferation in vitro and tumor growth in mice, while stable knockdown of TEAD4 inhibited proliferation in vitro and tumor growth in mice. Thus TEAD4 and KLF5, in collaboration, promoted TNBC cell proliferation and tumor growth in part by inhibiting p27 gene transcription. TEAD4 is a potential target and biomarker for the development of novel therapeutics for breast cancer.

Keywords: Hippo pathway; KLF5; TEAD4; TNBC; p27.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis*
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Gene Knockdown Techniques
  • Heterografts
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Muscle Proteins / metabolism*
  • Polymerase Chain Reaction
  • TEA Domain Transcription Factors
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • CDKN1B protein, human
  • DNA-Binding Proteins
  • KLF5 protein, human
  • Kruppel-Like Transcription Factors
  • Muscle Proteins
  • TEA Domain Transcription Factors
  • TEAD4 protein, human
  • Transcription Factors
  • Cyclin-Dependent Kinase Inhibitor p27