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.

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

Turco E;Defilippi P;
2019-01-01

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.
2019
10
1
3589
3606
https://www.nature.com/articles/s41467-019-11510-4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689091/
Breast cancer, PAK4, Cell signaling
Costa TDF, Zhuang T, Lorent J, Turco E, Olofsson H, Masia-Balague M, Zhao M, Rabieifar P, Robertson N, Kuiper R, Sjölund J, Spiess M, Hernández-Varas P, Rabenhorst U, Roswall P, Ma R, Gong X, Hartman J, Pietras K, Adams PD, Defilippi P, Strömblad S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1732767
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