Optimized NSAIDs for Breast Cancer Prevention
Final rept. 26 Mar 2004-25 Mar 2007
CALIFORNIA UNIV SAN DIEGO LA JOLLA
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Population studies have shown that women who use non-steroidal anti-inflammatory drugsNSAIDs develop breast cancer less frequently. However NSAIDs have side effects on thestomach and kidneys particularly at the high doses potentially required to prevent breastcancer. This project has focused on developing an optimized NSAID for breast cancerprevention that can be taken safely at high doses and determining its mechanisms of action. The side effects of NSAIDs are mainly due to inhibition of cyclo-oxygenase COX enzymes. Based on preliminary experiments we hypothesized that the preventative action of NSAIDs inbreast cancer is not solely due to COX inhibition but rather to alterations in the Wntsignaling pathway. Using a modified NSAID that does not inhibit the COX enzyme but does inhibit Wnt signaling we attempted chemoprevention of breast tumors in the MMTV-wnt1 and MMTV-neu transgenic mouse stains. Significant gene expression changes in a Wnt targetinvolved in cancer proliferation Cyclin D1 have been found. Unfortunately protein levelsof Cyclin D1 were unaffected and current experiments are characterizing the mechanism of this disparate finding. Regardless these data have already encouraged early biomarker based, clinical trials in women with breast cancer.
- Anatomy and Physiology
- Medicine and Medical Research