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. Adams, Paola Defilippi and Staffan Strömblad ()
Additional contact information
Tânia D. F. Costa: Karolinska Institutet
Ting Zhuang: Karolinska Institutet
Julie Lorent: Karolinska Institutet
Emilia Turco: University of Torino
Helene Olofsson: Karolinska Institutet
Miriam Masia-Balague: Karolinska Institutet
Miao Zhao: Karolinska Institutet
Parisa Rabieifar: Karolinska Institutet
Neil Robertson: Beatson Institute for Cancer Research
Raoul Kuiper: Karolinska Institutet
Jonas Sjölund: Lund University
Matthias Spiess: Karolinska Institutet
Pablo Hernández-Varas: Karolinska Institutet
Uta Rabenhorst: Karolinska Institutet
Pernilla Roswall: Karolinska Institutet
Ran Ma: Karolinska Institutet
Xiaowei Gong: Karolinska Institutet
Johan Hartman: Karolinska Institutet
Kristian Pietras: Lund University
Peter D. Adams: Beatson Institute for Cancer Research
Paola Defilippi: University of Torino
Staffan Strömblad: Karolinska Institutet

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11510-4

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