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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

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

Author

  • Tânia D F Costa
  • Ting Zhuang
  • Julie Lorent
  • Emilia Turco
  • Helene Olofsson
  • Miriam Masia-Balague
  • Miao Zhao
  • Parisa Rabieifar
  • Neil Robertson
  • Raoul Kuiper
  • Jonas Sjölund
  • Matthias Spiess
  • Pablo Hernández-Varas
  • Uta Rabenhorst
  • Pernilla Roswall
  • Ran Ma
  • Xiaowei Gong
  • Johan Hartman
  • Kristian Pietras
  • Peter D Adams
  • Paola Defilippi
  • Staffan Strömblad
Show all

Summary, in English

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.

Department/s

  • Experimental oncology
  • Division of Translational Cancer Research
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2019-08-09

Language

English

Pages

1-18

Publication/Series

Nature Communications

Volume

10

Issue

1

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cancer and Oncology

Status

Published

Research group

  • Experimental oncology

ISBN/ISSN/Other

  • ISSN: 2041-1723