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IRF-1-Dependent Apoptosis and Antiestrogen Sensitivity in Breast Cancer
Targeted inhibition of the estrogen receptor (ER) is one of the most successful therapeutic interventions available in the treatment of breast cancer. ER antagonists or antiestrogens exert their effects by preventing activation of the ER by estrogen. The antiestrogen Tamoxifen associates with the ER and prevents estrogen binding, while Faslodex (ICI 182,780) also prevents ER dimerization and facilitates receptor degradation. Faslodex is frequently effective in treating patients who have acquired resistance to Tamoxifen, and it is also receiving renewed interest as a first-line endocrine therapy. However, resistance to Faslodex is also likely to emerge as it becomes more commonly used in the clinic. In order to understand the molecular mechanisms of Faslodex resistance, our laboratory has developed an MCF7 cell culture model of Faslodex resistance. We have analyzed the gene expression profiles of our Faslodex-resistant cells and found that expression of the putative tumor suppressor interferon regulatory factor-1 (IRF-1) is downregulated. Moreover, we found that IRF-1 is an essential mediator of Faslodex sensitivity in breast cancer cells, and that a dominant-negative IRF-1 (dnIRF-1) abrogates the response to antiestrogens in MCF7 and T47D breast cancer cells by suppressing apoptosis. Therefore we hypothesize that IRF-1 controls the apoptotic response to antiestrogens by modulating the expression and activity of Bcl-2 and caspase family members, and that co-treatment with interferons and antiestrogens will restore growth inhibition and cell death in previously resistant cells by increasing the expression of IRF-1. We have generated MCF7 and T47D cell lines stably expressing a tetracycline-inducible dnIRF-1, and will use these reagents to identify the relevant IRF-1 target genes that control response to antiestrogens in Aim 1. In Aim 2, we will test multiple combinations of interferons and antiestrogens in the antiestrogen-resistant MCF7/LCC9 cell line to determine whether these drugs restore growth inhibition and apoptosis in vitro and either slow or prevent xenograft growth in vivo. These studies will clearly address our hypotheses, greatly enhance our understanding of the molecular mechanisms of antiestrogen resistance, and potentially lead to the design of new treatment regimens with increased efficacy and better outcomes for women with breast cancer.
Breast cancer that is resistant to endocrine or antiestrogen therapy is a significant clinical problem, since nearly one third of patients do not respond and the remaining 70% are likely to relapse in the future. However, antiestrogen therapy has been proven safe and effective and remains one of our best hopes for the control and elimination of this disease. Therefore it is essential that we understand how antiestrogen resistance works and use this knowledge to develop more effective treatments. Our research group has found that the tumor suppressor gene interferon regulatory factor-1 (IRF-1) is critical for breast cancer cells' response to the antiestrogens Tamoxifen and Faslodex (ICI 182,780), and that a loss of IRF-1 function severely impairs the cancer cell death (apoptosis) that is induced by antiestrogen treatment. Importantly, IRF-1 expression and function can in some cases be restored by treatment with interferons. The objectives of this study are to uncover how IRF-1 promotes cell death in response to antiestrogens and determine whether interferons can successfully be combined with antiestrogens to overcome resistance. We hypothesize that IRF-1 controls the expression and/or activity of specific cell death genes in response to antiestrogens and that combined treatment with interferons and antiestrogens will restore cell death in previously resistant breast cancer cells by increasing the expression of IRF-1. First, we will perform studies in cell culture to identify the relevant IRF-1 target genes that control response to antiestrogens. Next, we will study the combination of interferons alpha, beta, or gamma with the antiestrogens Tamoxifen and Faslodex in cell culture to determine whether these drugs restore cell death to antiestrogen-resistant breast cancer cells. We will also investigate the ability of the interferon/antiestrogen combination to slow or prevent tumor growth in mouse models. This work will help us understand how antiestrogen resistance works and has great potential to initiate preclinical combinatorial drug studies. Therefore, this project is novel, innovative, and timely in our efforts to overcome the significant clinical problem of antiestrogen resistance.