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PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer
Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden;Xinxiang Med Univ, Sch Lab Med, Henan Collaborat Innovat Ctr Mol Diag & Lab Med, Xinxiang 453003, Henan, Peoples R China.ORCID iD: 0000-0002-6308-1253
Karolinska Inst, Dept Oncol Pathol, SE-17177 Solna, Sweden.
Univ Torino, Dept Genet Biol & Biochem, I-10126 Turin, Italy.
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 3589Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 10, article id 3589
National Category
Cancer and Oncology
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URN: urn:nbn:se:uu:diva-398817DOI: 10.1038/s41467-019-11510-4ISI: 000480234500003PubMedID: 31399573OAI: oai:DiVA.org:uu-398817DiVA, id: diva2:1378775
Funder
Swedish Research CouncilSwedish Cancer SocietyKnut and Alice Wallenberg FoundationThe Cancer Research Funds of RadiumhemmetScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceAvailable from: 2019-12-13 Created: 2019-12-13 Last updated: 2019-12-13Bibliographically approved

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