|DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.|
|PMID: 20028875 Owner: NLM Status: MEDLINE|
|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.|
|Colleen Fordyce; Tim Fessenden; Curtis Pickering; Jason Jung; Veena Singla; Hal Berman; Thea Tlsty|
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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|
|Title: Cancer prevention research (Philadelphia, Pa.) Volume: 3 ISSN: 1940-6215 ISO Abbreviation: Cancer Prev Res (Phila) Publication Date: 2010 Feb|
|Created Date: 2010-02-05 Completed Date: 2010-04-23 Revised Date: 2014-09-12|
Medline Journal Info:
|Nlm Unique ID: 101479409 Medline TA: Cancer Prev Res (Phila) Country: United States|
|Languages: eng Pagination: 190-201 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Ataxia Telangiectasia Mutated Proteins
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
Gene Expression Profiling
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
|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|
|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 22.214.171.124/Cyclooxygenase 2; EC 126.96.36.199/ATM protein, human; EC 188.8.131.52/Ataxia Telangiectasia Mutated Proteins; EC 184.108.40.206/Protein-Serine-Threonine Kinases|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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