Journal
CANCER PREVENTION RESEARCH
Volume 3, Issue 2, Pages 190-201Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1940-6207.CAPR-09-0229
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Funding
- National Cancer Institute/NIH [R01 CA122024, R01 CA097214, P01 CA107584]
- CIRM [RS1-00444-1]
- CBCRP [A110281]
- Avon Foundation [07-2007-074]
- DOD [DAMD17-03-1-0424]
- NIH [RO1]
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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 gamma H2AX, 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. Cancer Prev Res; 3(2); 190-201. (C) 2010 AACR.
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