ArticlePloS one2007
Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation.
Article in PloS one, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 86 citations in OpenAlex.
- ER stress tolerance is regulated by copper-dependent PERK kinase activity.Cell reports · 2025Article
- PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape.Cell reports · 2025Article
- Review
- Review
- mTOR pathway occupies a central role in the emergence of latent cancer cells.Cell death & disease · 2024Review
- A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of Quiescent Cancer Cells.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP).International journal of molecular sciences · 2023Review
- The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer.Human molecular genetics · 2023Review
- The unfolded protein response (UPR) pathway: the unsung hero in breast cancer management.Apoptosis : an international journal on programmed cell death · 2023Review
- SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer.iScience · 2022Article
- ECM dimensionality tunes actin tension to modulate endoplasmic reticulum function and spheroid phenotypes of mammary epithelial cells.The EMBO journal · 2022Article
- Paradoxical effects of DNA tumor virus oncogenes on epithelium-derived tumor cell fate during tumor progression and chemotherapy response.Signal transduction and targeted therapy · 2021Article
- Comprehensive understanding of anchorage-independent survival and its implication in cancer metastasis.Cell death & disease · 2021Review
- Protein kinase-like ER kinase (PERK) regulates autophagy of hemocytes in antiviral immunity of Pacific oysterFish and shellfish immunology reports · 2020Article
- Role of the AMPK/ACC Signaling Pathway in TRPP2-Mediated Head and Neck Cancer Cell Proliferation.BioMed research international · 2020Article
- Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis.International journal of molecular sciences · 2019Review
- Mechanism and medical implications of mammalian autophagy.Nature reviews. Molecular cell biology · 2018Review
- Functional significance of co-occurring mutations inOncotarget · 2018Article
- Interplay between P-Glycoprotein Expression and Resistance to Endoplasmic Reticulum Stressors.Molecules (Basel, Switzerland) · 2018Review
- The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion.Journal of molecular biology · 2017Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Endoplasmic reticulum (ER) stress signaling can be mediated by the ER kinase PERK, which phosphorylates its substrate eIF2alpha. This in turn, results in translational repression and the activation of downstream programs that can limit cell growth through cell cycle arrest and/or apoptosis. These responses can also be initiated by perturbations in cell adhesion. Thus, we hypothesized that adhesion-dependent regulation of PERK signaling might determine cell fate. We tested this hypothesis in a model of mammary acini development, a morphogenetic process regulated in part by adhesion signaling. Here we report a novel role for PERK in limiting MCF10A mammary epithelial cell proliferation during acinar morphogenesis in 3D Matrigel culture as well as in preventing mammary tumor formation in vivo. We show that loss of adhesion to a suitable substratum induces PERK-dependent phosphorylation of eIF2alpha and selective upregulation of ATF4 and GADD153. Further, inhibition of endogenous PERK signaling during acinar morphogenesis, using two dominant-negative PERK mutants (PERK-DeltaC or PERK-K618A), does not affect apoptosis but results instead in hyper-proliferative and enlarged lumen-filled acini, devoid of proper architecture. This phenotype correlated with an adhesion-dependent increase in translation initiation, Ki67 staining and upregulation of Laminin-5, ErbB1 and ErbB2 expression. More importantly, the MCF10A cells expressing PERKDeltaC, but not a vector control, were tumorigenic in vivo upon orthotopic implantation in denuded mouse mammary fat pads. Our results reveal that the PERK pathway is responsive to adhesion-regulated signals and that it is essential for proper acinar morphogenesis and in preventing mammary tumor formation. The possibility that deficiencies in PERK signaling could lead to hyperproliferation of the mammary epithelium and increase the likelihood of tumor formation, is of significance to the understanding of breast cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.