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

Costa, T. D. F. et al. (2019) PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer. Nature Communications, 10, 3589. (doi: 10.1038/s41467-019-11510-4) (PMID:31399573) (PMCID:PMC6689091)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Robertson, Mr Neil and Adams, Professor Peter
• Authors: Costa, T. D. F., 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, P. D., Defilippi, P., and Strömblad, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Nature Communications 10: 3589
• Publisher Policy: Reproduced under a Creative Commons License