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

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 AdamsPaola Defilippi, Staffan Strömblad

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3589
Pages (from-to)1-18
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Aug 9

Subject classification (UKÄ)

  • Cancer and Oncology

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