New signaling pathway controlling breast cancer
Cells exposed to cancer-driving mutations respond by triggering a stress reaction called cellular senescence, which halts cell proliferation and thereby constitutes the major protective barrier to cancer. Researchers at Karolinska Institutet have now discovered a previously unknown signaling pathway that controls cellular senescence in breast cancer.
The study, published in the journal Nature Communications, was led by Doctoral student Tânia Costa together with Professor Staffan Strömblad at the Department of Biosciences and Nutrition. Together with their colleagues, they show that the signaling protein PAK4 is overexpressed in breast cancer and correlates to poor prognosis in breast cancer patients.
The study further shows that PAK4 can cause mammary gland cells that are exposed to cancer-driving mutations to pass through the senescence barrier to cancer.
“By inhibiting PAK4, we can also restore cellular senescence when cancer has occurred, this by inducing two genes, RelB and CEBPß, involved in the control of gene expression leading to senescence. Inhibition of PAK4 could therefore be developed as a novel therapy against breast cancer, comments Professor Strömblad. “These discoveries could lead not only to new strategies to treat cancer, but also to affect aging and other diseases where cellular senescence is essential.”
This study was supported by grants from the Swedish Research Council, Radiumhemmets Forskningsfonder and the Swedish Cancer Society, the Breast Cancer Theme Center at Karolinska Institutet. and the Portuguese Foundation for Science and Technology.
PAK4 suppresses RELB to prevent senescence like growth arrest in breast cancer
Tânia D.F. Costa, Ting Zhuang, Julie Lorent, Emilia Turco, Helene Olofsson, Miriam Masia-Balague, Miao Zhao, Parisa Rabieifar, Neil Robertson, Raoul Kuiper, Jonas Sjölund, Matthias Spiess, Pablo Hernández Varas, Uta Rabenhorst, Pernilla Roswall, Ran Ma, Xiaowei Gong, Johan Hartman, Kristian Pietras, Peter D. Adams, Paola Defilippi, Staffan Strömblad
Nature Communications, online 9 August 2019, doi: 10.1038/s41467-019-11510-4