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Cited by 41Inflammatory mediators and NSAID effectsTelomeres, Telomerase, and SenescenceCancer-related Molecular Pathways

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DNA Damage Drives an Activin A–Dependent Induction of Cyclooxygenase-2 in Premalignant Cells and Lesions

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Fordyce, Colleen, Fessenden, Tim, Pickering, Curtis, Jung, Jason, Singla, Veena, Berman, Hal, Tlsty, Thea·2010·Cancer Prevention Research
DOI 10.1158/1940-6207.capr-09-0229PMC PMC2954106

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Abstract

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the synthesis of prostaglandins. Its overexpression induces numerous tumor-promoting phenotypes and is associated with cancer metastasis and poor clinical outcome. Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits. Systemic complications of COX-2 inhibition could be avoided by specifically decreasing COX-2 expression in epithelial cells. To that end, we have investigated the signal transduction pathway regulating the COX-2 expression in response to DNA damage in breast epithelial cells. In variant human mammary epithelial cells that have silenced p16 (vHMEC), double-strand DNA damage or telomere malfunction results in a p53- and activin A–dependent induction of COX-2 and continued proliferation. In contrast, telomere malfunction in HMEC with an intact p16/Rb pathway induces cell cycle arrest. Importantly, in ductal carcinoma in situ lesions, high COX-2 expression is associated with high γH2AX, TRF2, activin A, and telomere malfunction. These data show that DNA damage and telomere malfunction can have both cell-autonomous and cell-nonautonomous consequences and can provide a novel mechanism for the propagation of tumorigenesis. Cancer Prev Res; 3(2); 190–201

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  • Double-stranded DNA breaks can promote production of IL-6 and activin A.

    “Double-stranded DNA breaks can promote the production of IL-6 and the TGFβ family ligand activin A69,70.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [70]

    The Results section, “Telomere Malfunction Induces Activin A” (page unavailable), reports that activin A mRNA and protein were preferentially induced by double-strand DNA damage in variant human mammary epithelial cells. The passages found do not report that such breaks promote IL-6 production, so the IL-6 part of the attributed claim is unsupported by this paper. (LLM, conf=0.86)

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Research works printed but not linked: 48

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Metadata

Authors
Fordyce, C., Fessenden, T., Pickering, C., Jung, J., Singla, V., Berman, H., & Tlsty, T.
Affiliations
University of California, San Francisco (US)
Corresponding author
Tlsty, Thea
ORCID
Venue
Cancer Prevention Research
Publisher
American Association for Cancer Research (AACR)
Published
2010-02-01
Volume
3
Issue
2
Pages
190-201
ISSN
  • 1940-6207 (ISSN-L)
  • 1940-6215
DOI
10.1158/1940-6207.capr-09-0229
PMC
PMC2954106
OpenAlex
W2097968887
Cited by
41
References
57
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 3
FWCI
2.40
Type
journal article
Language
en
Open access
Locations
  • Cancer Prevention Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Defense
  • Avon Foundation for Women (07-2007-074)
  • California Breast Cancer Research Program
  • Johns Hopkins University
  • Virginia Commonwealth University
  • National Institutes of Health (NIH-R01)
  • Kaiser Foundation Research Institute
  • National Cancer Institute (CA097214, R01CA097214, CA107584, P01CA107584, R01CA122024)
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
cyclooxygenase-2, DNA damage, activin A, telomere dysfunction, p53, p16/Rb pathway, breast epithelial cells, ductal carcinoma in situ, precancerous lesions, γH2AX, TRF2, cell cycle arrest, COX-2 inhibitors, carcinogenesis, signal transduction
MeSH terms
Breast Neoplasms, Carcinoma in Situ, DNA Damage, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Neoplasm Proteins, Precancerous Conditions, Blotting, Western, Signal Transduction, Gene Expression, Tumor Suppressor Protein p53, Retinoblastoma Protein, Telomere, Protein Serine-Threonine Kinases, Carcinoma, Ductal, Breast, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p16, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Tumor Suppressor Proteins, Activins, Telomeric Repeat Binding Protein 2, Cyclooxygenase 2, Ataxia Telangiectasia Mutated Proteins

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