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PMID: 20028875 Published · ppublish English 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.

DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.

Cancer prevention research (Philadelphia, Pa.) ·Vol. 3 ·No. 2 ·2010-02-00 ·Pages 190-201

Fordyce C, Fessenden T, Pickering C, Jung J, Singla V, Berman H, Tlsty T

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 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.

MeSH Terms
Activins/metabolism Ataxia Telangiectasia Mutated Proteins Blotting, Western Breast Neoplasms/genetics,metabolism,pathology Carcinoma in Situ/genetics,metabolism,pathology Carcinoma, Ductal, Breast/genetics,metabolism,pathology Cell Cycle Proteins/genetics,metabolism Cyclin-Dependent Kinase Inhibitor p16 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
Chemicals
CDKN2A protein, human Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p16 DNA-Binding Proteins Neoplasm Proteins Retinoblastoma Protein Telomeric Repeat Binding Protein 2 Tumor Suppressor Protein p53 Tumor Suppressor Proteins activin A Activins Cyclooxygenase 2 ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Fordyce Colleen
Department of Pathology, University of California, San Francisco, 94143, USA.
Fessenden Tim
Pickering Curtis
Jung Jason
Singla Veena
Berman Hal
Tlsty Thea
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Article Info
Journal
Cancer prevention research (Philadelphia, Pa.)
Abbr.
Cancer Prev Res (Phila)
ISSN
1940-6215
DOI
10.1158/1940-6207.CAPR-09-0229
Published
2010-02-00
Epub
2009-00-22
Pages
190-201
Language
English
Region
United States
NLM ID
101479409
PMCID
PMC2954106
Subset
IM
Grants
NCI NIH HHS · R01 CA097214-06A1 · United States
NCI NIH HHS · R01 CA122024 · United States
NCI NIH HHS · R01 CA097214 · United States
NCI NIH HHS · P01 CA107584-03 · United States
NCI NIH HHS · P01 CA107584 · United States
NCI NIH HHS · R01 CA097214-01A1 · United States
External Links
PubMed source DOI: 10.1158/1940-6207.CAPR-09-0229 PMC Full Text View journal details
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