PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer

Research output: Contribution to journalArticle

Abstract

Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 - RELB - C/EBPβ axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPβ. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.

Details

Authors
  • Tânia D F Costa
  • Ting Zhuang
  • Julie Lorent
  • Emilia Turco
  • Helene Olofsson
  • Miriam Masia-Balague
  • Miao Zhao
  • Parisa Rabieifar
  • Neil Robertson
  • Raoul Kuiper
  • Matthias Spiess
  • Pablo Hernández-Varas
  • Uta Rabenhorst
  • Pernilla Roswall
  • Ran Ma
  • Xiaowei Gong
  • Johan Hartman
  • Peter D Adams
  • Paola Defilippi
  • Staffan Strömblad
Organisations
External organisations
  • Karolinska Institutet
  • University of Turin
  • Beatson Institute for Cancer Research
  • University of Glasgow
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Article number3589
Pages (from-to)1-18
JournalNature Communications
Volume10
Issue number1
Publication statusPublished - 2019 Aug 9
Publication categoryResearch
Peer-reviewedYes