Data di Pubblicazione:
2019
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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Breast cancer, PAK4, Cell signaling
Elenco autori:
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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