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Cyclooxygense-2 Protein and Tamoxifen Resistance in Breast Cancer
Tamoxifen is effective for treating patients with estrogen receptor positive (ER+) breast cancer. However, many ER+ breast tumors do not respond to tamoxifen. The underlying causes of tamoxifen resistance are largely unknown, but understanding the mechanisms by which this resistance is induced will allow us to design effective strategies to overcome it and further improve the effectiveness of tamoxifen as a breast cancer therapeutic agent. High levels of the Cyclooxygenase-2 (COX-2) protein have been found in ER+ breast tumors, and these high levels of COX-2 are associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce tamoxifen resistance in ER+ breast tumors, thus reducing the survival rate of patients with such tumors. We found that human breast cancer cells stably transfected with plasmids encoding the COX-2 gene, although ER+, were resistant to tamoxifen, and that selective inhibitors of COX-2 increased the inhibitory effects of tamoxifen in COX-2-overexpressing cells. We also found that the COX-2 product prostaglandin E2 (PGE2) blocked tamoxifen's inhibitory effects. Our hypothesis is that high levels of COX-2 induce tamoxifen resistance in ER+ breast tumors and that concomitant treatment with tamoxifen and COX-2 inhibitors will increase those tumors’ sensitivity to tamoxifen. We will test our hypothesis using two Specific Aims. In Aim 1, we will use xenograft models to demonstrate that COX-2 induces tamoxifen resistance in human breast tumors, and that COX-2 inhibitors increase tamoxifen-induced inhibition of tumor growth. In Aim 2, we will identify the mechanisms by which COX-2 and PGE2 induce tamoxifen resistance in breast cancer cells. Many ER+ breast tumors are resistant to tamoxifen; the underlying mechanisms of this resistance remain elusive. This project is innovative because it demonstrates for the first time that COX-2 is involved in tamoxifen resistance in ER+ breast tumors and that COX-2 inhibitors can overcome that resistance. The doses of COX-2 inhibitors that can be safely administered are known, and combining tamoxifen with these agents is feasible. We expect that this novel drug combination will improve the usefulness of tamoxifen as a breast cancer therapeutic agent. The proposed mechanistic studies should further enhance our ability to design alternative strategies to overcome tamoxifen resistance and save many patients' lives.
Breast cancer patients, whose tumors contain high levels of hormone receptors, are often treated with antihormonal drugs such as tamoxifen. Tamoxifen has been used successfully to treat all stages of breast cancer in patients of all ages. But many hormone receptor-positive breast tumors do not respond to tamoxifen. We do not know what causes these breast tumors to be unresponsive to tamoxifen. A protein called Cyclooxygenase-2 (COX-2) has been found at high levels in hormone receptor-positive breast tumors; the COX-2 protein is known to protect cancer cells from being killed by cancer drugs. We have found that tamoxifen cannot kill hormone receptor-positive breast cancer cells when those cells contain high levels of COX-2, and that anti-COX-2 drugs allow tamoxifen to kill cancer cells again. Therefore, we hypothesize that patients whose hormone receptor-positive breast tumors have high levels of COX-2 will not benefit from tamoxifen unless it is combined with anti-COX-2 drugs. We will test our hypothesis using two Aims. In Aim 1, we will extend our cell line studies and use animal models to prove that high levels of COX-2 cause breast tumors to be unresponsive to tamoxifen and to show that anti-COX-2 drugs can overcome the problem and allow tamoxifen to kill breast tumors. In Aim 2, we will use cell line models to study how COX-2 prevents tamoxifen from killing breast cancer cells. Our overall goal is to understand why some breast tumors are unresponsive to tamoxifen and how we can convert those unresponsive breast tumors to become sensitive to tamoxifen. By the end of this project, we expect to have enough data to allow us to translate our concept into treatment for human patients with breast cancer. In clinical trials, we will ultimately determine whether adding anti-COX-2 drugs increases tamoxifen’s ability to kill breast tumors and prolong patients’ lives. Assays that can identify breast tumors that have high levels of hormone receptors are well established, and those that measure COX-2 levels, which have been established in many laboratories, could easily be incorporated into routine assays. Also, the doses of tamoxifen and anti-COX-2 drugs that can be safely and effectively administered are known. Identifying and enrolling patients into future clinical trials is very feasible. Therefore, this project is highly applicable to breast cancer treatment and should have a major and immediate effect on the fight against breast cancer and save many patients' lives.