The transition of localized breast cancer to metastatic disease is a major contributor to increased disability and death associated with advanced disease. Treatment options are limited once metastatic status has been reached; although metastases originate from the primary tumor, fundamental shifts in cell phenotype occur during the stages of dissemination, formation of micro-metastases, and the growth of metastases themselves. The origin and influence of these differences remains poorly understood. There is thus a great need for small molecule tools that modulate uniquely activated metastatic pathways in order to identify specific and effective therapeutic options. Through this work we will both provide small molecule tools targeted to a cellular invasion pathways that are uniquely activated in metastasis and test if pharmacological inhibition of these pathways can block metastatic phenotypes in breast cancer. This will be accomplished through targeting a dysregulated transcription factor complex formed between the ETV/PEA3 transcriptional activators (ETV1, ETV4, and ETV5) and the coactivator Med25 with natural product-based modulators. Taken together, these studies will define new pathways for therapeutic targeting of advanced cancer and the natural product modulators will serve as starting points for the long-term development of novel therapies.
Activation of the ETV/PEA3 family of transcriptional activators is associated with tumorigenesis and metastasis in a range of cancers; genetic deletion of ETV/PEA3 has also been shown to inhibit metastasis in vivo. In this project we will use an innovative transcriptional modulator discovery strategy to identify natural product-based inhibitors and activators of the ETV/PEA3 activators. These molecules will be used to dissect the role of the ETV/PEA3?Med25 complex in tumor growth and metastasis in vitro and in an in vivo model of breast cancer. These molecules will be broadly useful probes for chemical genetic studies of transcriptional dysregulation in human disease and serve as starting points for the development of therapeutic agents that alter ETV/PEA3 function.
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