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Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation

Sharon J Sequeira1, Aparna C Ranganathan, Alejandro P Adam

  • 1Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, New York, United States of America.

Plos One
|July 20, 2007
PubMed

Insights

Endoplasmic reticulum (ER) stress kinase PERK limits mammary cell proliferation and prevents tumor formation by responding to cell adhesion signals. Its deficiency leads to hyperproliferation and architectural defects during mammary gland development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Endoplasmic reticulum (ER) stress signaling, mediated by ER kinase PERK, regulates cell growth via eIF2alpha phosphorylation, impacting cell cycle arrest and apoptosis.
  • Cell adhesion perturbations can also trigger these growth-limiting responses, suggesting a link between adhesion and ER stress pathways.

Purpose of the Study:

  • To investigate the hypothesis that adhesion-dependent regulation of PERK signaling dictates cell fate.
  • To elucidate the role of PERK in mammary acini development and mammary tumor formation.

Main Methods:

  • Utilized a model of mammary acini development in 3D Matrigel culture.
  • Employed dominant-negative PERK mutants (PERK-DeltaC, PERK-K618A) to inhibit endogenous PERK signaling.
  • Assessed cell proliferation, apoptosis, acini architecture, and gene expression.
  • Evaluated tumorigenicity of MCF10A cells in vivo via orthotopic implantation.

Main Results:

  • Loss of cell adhesion induced PERK-dependent eIF2alpha phosphorylation and upregulated ATF4 and GADD153.
  • Inhibition of PERK signaling resulted in hyper-proliferative, architecturally abnormal acini without affecting apoptosis.
  • PERK inhibition correlated with increased translation initiation, Ki67 staining, and upregulation of Laminin-5, ErbB1, and ErbB2.
  • MCF10A cells expressing PERK-DeltaC were tumorigenic in vivo, unlike vector controls.

Conclusions:

  • The PERK pathway is responsive to adhesion-regulated signals and is crucial for proper mammary acinar morphogenesis.
  • PERK signaling is essential for limiting mammary epithelial cell proliferation and preventing mammary tumor formation.
  • Deficiencies in PERK signaling may contribute to mammary epithelial hyperproliferation and increase breast cancer risk.

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