Document Detail


DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.
MedLine Citation:
PMID:  20028875     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Colleen Fordyce; Tim Fessenden; Curtis Pickering; Jason Jung; Veena Singla; Hal Berman; Thea Tlsty
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Publication Detail:
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:
Title:  Cancer prevention research (Philadelphia, Pa.)     Volume:  3     ISSN:  1940-6215     ISO Abbreviation:  Cancer Prev Res (Phila)     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-05     Completed Date:  2010-04-23     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  101479409     Medline TA:  Cancer Prev Res (Phila)     Country:  United States    
Other Details:
Languages:  eng     Pagination:  190-201     Citation Subset:  IM    
Affiliation:
Department of Pathology, University of California, San Francisco, 94143, USA.
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MeSH Terms
Descriptor/Qualifier:
Activins / 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:
P01 CA107584/CA/NCI NIH HHS; P01 CA107584/CA/NCI NIH HHS; P01 CA107584-03/CA/NCI NIH HHS; R01 CA097214/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:
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

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