| DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions. | |
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MedLine Citation:
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PMID: 20028875 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 gammaH2AX, 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. |
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Authors:
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Colleen Fordyce; Tim Fessenden; Curtis Pickering; Jason Jung; Veena Singla; Hal Berman; Thea Tlsty |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2009-12-22 |
Journal Detail:
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Title: Cancer prevention research (Philadelphia, Pa.) Volume: 3 ISSN: 1940-6215 ISO Abbreviation: Cancer Prev Res (Phila) Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-02-05 Completed Date: 2010-04-23 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 101479409 Medline TA: Cancer Prev Res (Phila) Country: United States |
Other Details:
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Languages: eng Pagination: 190-201 Citation Subset: IM |
Affiliation:
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Department of Pathology, University of California, San Francisco, 94143, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Activins
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metabolism* Blotting, Western Breast Neoplasms / genetics*, metabolism, pathology Carcinoma in Situ / genetics, metabolism, pathology Carcinoma, Ductal, Breast / genetics, metabolism, pathology Cell Cycle Proteins / genetics, metabolism Cyclooxygenase 2 / biosynthesis* DNA Damage / genetics* DNA-Binding Proteins / genetics, metabolism Enzyme-Linked Immunosorbent Assay Female Gene Expression Gene Expression Profiling Humans Immunohistochemistry Neoplasm Proteins / genetics, metabolism Oligonucleotide Array Sequence Analysis Precancerous Conditions / genetics*, metabolism Protein-Serine-Threonine Kinases / genetics, metabolism Retinoblastoma Protein / genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / physiology Telomere / genetics, metabolism, pathology Telomeric Repeat Binding Protein 2 / genetics, metabolism Tumor Suppressor Protein p53 / genetics, metabolism Tumor Suppressor Proteins / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA107584/CA/NCI NIH HHS; P01 CA107584-03/CA/NCI NIH HHS; R01 CA097214/CA/NCI NIH HHS; R01 CA097214-01A1/CA/NCI NIH HHS; R01 CA097214-06A1/CA/NCI NIH HHS; R01 CA122024/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Neoplasm Proteins; 0/P16 protein, human; 0/Retinoblastoma Protein; 0/Telomeric Repeat Binding Protein 2; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 0/activin A; 104625-48-1/Activins; EC 1.14.99.1/Cyclooxygenase 2; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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