Tamoxifen (Tam) is the most frequently prescribed drug for breast cancer. Its effectiveness is limited, however, by the development of acquired resistance in most patients. Mechanisms for this acquired resistance are largely unknown, but their clarification would have profound clinical implications for new strategies to prevent, delay, or reverse the development of resistance. Using an in vivo model, we have found that one form of resistance is due to the acquired ability of tumors after chronic Tam therapy to be stimulated rather than inhibited by Tam; clinical observations also support this finding. How Tam could stimulate tumor growth after a prolonged period of growth suppression is unknown, though we have found that Tam-stimulated growth is not due to altered systemic or tumor metabolism of Tam. Nor is this form of resistance due to loss or mutation of the estrogen receptor (ER). We also found that Tam-stimulated tumor growth can be blocked by the pure steroidal antiestrogen ICl 182,780, which works by a different mechanism than Tam - this has led directly to a clinical trial by collaborators in England. Recent data suggest two hypotheses that we now propose to investigate to explain Tam-stimulated growth. First, ER contains two transcriptional activating regions, including a constitutively active albeit weak domain known as AF-1. It has been hypothesized that the agonist activity of Tam observed in some tissues may be due to enhanced AF-1 activity caused by tissue-specific factors that interact with ER. Second, ER can modify gene expression not only through the estrogen response element on target genes, but also by directly interacting with other transcription factors including a factor called AP-1. We have now found that Tam-stimulated tumor growth is associated with increased AP-1 activity, perhaps as a result of Tam- induced oxidant stress which is a potent inducer of AP-1. We therefore hypothesize that this increased AP-1 activity may result in tumor growth stimulation after chronic Tam treatment, so that anti-oxidant therapy may be able to delay the emergence of resistance. The following specific aims are proposed to address these two hypotheses. (1) We will determine whether Tam-stimulated growth is associated with increased ER AF-1 transcriptional activity, and then identify ER- interacting accessory proteins that may be involved. (2) We will determine whether Tam-stimulated growth is due to altered AP-1 activity as a result of oxidant stress. Then we will explore strategies to delay or prevent Tam-stimulated growth by anti-oxidant therapy. These studies should provide important new insights into mechanisms of tamoxifen resistance, and may thereby offer new strategies to be exploited in future clinical trials.
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