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

Tânia D F Costa1, Ting Zhuang1,2, Julie Lorent3

  • 1Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden.

Nature Communications
|August 11, 2019
PubMed

Insights

The protein kinase PAK4 promotes breast cancer by preventing cellular senescence, a natural growth arrest. Inhibiting PAK4 may offer a new therapeutic strategy for breast cancer patients.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Cellular senescence is a crucial tumor suppressor mechanism that cancer cells must overcome.
  • Overcoming growth restriction, including senescence evasion, is a hallmark of cancer development.
  • The role of PAK4 in breast cancer and its potential involvement in senescence evasion requires further elucidation.

Purpose of the Study:

  • To investigate the role of PAK4 in breast cancer development and progression.
  • To determine if PAK4 contributes to the evasion of cellular senescence in breast cancer.
  • To elucidate the molecular mechanisms by which PAK4 influences senescence.

Main Methods:

  • Analysis of PAK4 expression in human breast cancer subtypes and correlation with patient outcomes.
  • Generation of genetically modified mouse models with altered PAK4 expression (overexpression and gene depletion).
  • In vitro, in vivo, and ex vivo experiments to assess the effect of PAK4 on senescence in breast cancer cells and normal mammary epithelial cells.
  • Investigation of the PAK4-RELB-C/EBPβ signaling axis and its role in regulating senescence.

Main Results:

  • PAK4 is overexpressed across all human breast cancer subtypes and linked to poor patient prognosis.
  • MMTV-PAK4 overexpression drives spontaneous mammary tumors in mice, while PAK4 depletion delays tumor growth.
  • PAK4 actively prevents senescence-like growth arrest in breast cancer cells, but is dispensable in non-immortalized cells.
  • PAK4 overexpression abrogates oncogene-induced senescence in normal human mammary epithelial cells.
  • A signaling axis involving PAK4, RELB, and C/EBPβ regulates senescence, with PAK4 phosphorylation of RELB being critical for its function.

Conclusions:

  • PAK4 is a key promoter of breast cancer by enabling cancer cells to evade oncogene-induced senescence.
  • The PAK4-RELB-C/EBPβ pathway is a critical regulator of senescence evasion in breast cancer.
  • These findings identify PAK4 as a potential therapeutic target, revealing a selective vulnerability in cancer cells.

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