PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer
(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.
(Less)
- author
- organization
- publishing date
- 2019-08-09
- 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
- 2024-09-18 08:18:22
@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}}, }