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

Costa, Tânia D F ; Zhuang, Ting ; Lorent, Julie ; Turco, Emilia ; Olofsson, Helene ; Masia-Balague, Miriam ; Zhao, Miao ; Rabieifar, Parisa ; Robertson, Neil and Kuiper, Raoul , et al. (2019) In Nature Communications 10(1). p.1-18
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
10
issue
1
article number
3589
pages
1 - 18
publisher
Nature Publishing Group
external identifiers
  • scopus:85070584711
  • pmid:31399573
ISSN
2041-1723
DOI
10.1038/s41467-019-11510-4
language
English
LU publication?
yes
id
3b45b292-9cf7-44e8-bdc4-be24df4f2bf4
date added to LUP
2019-08-21 15:40:35
date last changed
2022-10-01 19:25:44
@article{3b45b292-9cf7-44e8-bdc4-be24df4f2bf4,
  abstract     = {{<p>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.</p>}},
  author       = {{Costa, Tânia D F and Zhuang, Ting and Lorent, Julie and Turco, Emilia and Olofsson, Helene and Masia-Balague, Miriam and Zhao, Miao and Rabieifar, Parisa and Robertson, Neil and Kuiper, Raoul and Sjölund, Jonas and Spiess, Matthias and Hernández-Varas, Pablo and Rabenhorst, Uta and Roswall, Pernilla and Ma, Ran and Gong, Xiaowei and Hartman, Johan and Pietras, Kristian and Adams, Peter D and Defilippi, Paola and Strömblad, Staffan}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{1}},
  pages        = {{1--18}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-11510-4}},
  doi          = {{10.1038/s41467-019-11510-4}},
  volume       = {{10}},
  year         = {{2019}},
}