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

Costa, Tânia D F (author)
Karolinska Institutet,Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Zhuang, Ting (author)
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
Lorent, Julie (author)
Karolinska Institutet,Karolinska Inst, Dept Oncol Pathol, SE-17177 Solna, Sweden
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Turco, Emilia (author)
University of Turin,Univ Torino, Dept Genet Biol & Biochem, I-10126 Turin, Italy
Olofsson, Helene (author)
Karolinska Institutet,Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Masia-Balague, Miriam (author)
Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Zhao, Miao (author)
Uppsala universitet,Neuroonkologi,Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Rabieifar, Parisa (author)
Karolinska Institutet,Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Robertson, Neil (author)
Beatson Institute for Cancer Research,Beatson Inst Canc Res Bearsden, Glasgow G61 1BD, Lanark, Scotland
Kuiper, Raoul (author)
Karolinska Institutet,Karolinska Inst, Dept Lab Med, SE-14157 Huddinge, Sweden
Sjölund, Jonas (author)
Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Experimentell onkologi,Forskargrupper vid Lunds universitet,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Experimental oncology,Lund University Research Groups,Lund Univ, Dept Lab Med, Div Translat Canc Res, SE-22381 Lund, Sweden
Spiess, Matthias (author)
Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Hernández-Varas, Pablo (author)
Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Rabenhorst, Uta (author)
Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Roswall, Pernilla (author)
Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, SE-17177 Solna, Sweden
Ma, Ran (author)
Karolinska Institutet,Karolinska Inst, Dept Oncol Pathol, SE-17177 Solna, Sweden
Gong, Xiaowei (author)
Karolinska Institutet,Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
Hartman, Johan (author)
Karolinska Institutet,Karolinska Inst, Dept Oncol Pathol, SE-17177 Solna, Sweden
Pietras, Kristian (author)
Karolinska Institutet,Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Experimentell onkologi,Forskargrupper vid Lunds universitet,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Experimental oncology,Lund University Research Groups,Lund Univ, Dept Lab Med, Div Translat Canc Res, SE-22381 Lund, Sweden;Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, SE-17177 Solna, Sweden
Adams, Peter D (author)
Beatson Institute for Cancer Research,University of Glasgow,Beatson Inst Canc Res Bearsden, Glasgow G61 1BD, Lanark, Scotland;Univ Glasgow, Coll Med Vet & Life Sci, Inst Canc Sci, Glasgow G12 8QQ, Lanark, Scotland;Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA
Defilippi, Paola (author)
University of Turin,Univ Torino, Dept Genet Biol & Biochem, I-10126 Turin, Italy
Strömblad, Staffan (author)
Karolinska Institutet,Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden
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 (creator_code:org_t)
2019-08-09
2019
English.
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1-18
Related links:
http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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https://doi.org/10.1...
http://kipublication...
https://urn.kb.se/re...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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