title: DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.
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.
authors.affiliation: Department of Pathology, University of California, San Francisco, 94143, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Fordyce
authors.forename: Tim
authors.initials: T
authors.lastname: Fessenden
authors.forename: Curtis
authors.initials: C
authors.lastname: Pickering
authors.forename: Jason
authors.initials: J
authors.lastname: Jung
authors.forename: Veena
authors.initials: V
authors.lastname: Singla
authors.forename: Hal
authors.initials: H
authors.lastname: Berman
authors.forename: Thea
authors.initials: T
authors.lastname: Tlsty
mesh_terms: D028341:Activins / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D016615:Telomere / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000614131:CDKN2A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C422405:activin A; D028341:Activins; D051546:Cyclooxygenase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases