1. Reprogramming of the chromatin landscape is a critical component to the transcriptional response in breast cancer. Effects of sex hormones such as estrogens and progesterone have been well described to have a critical impact on breast cancer proliferation. However, the complex network of the chromatin landscape, enhancer regions and mode of function of steroid receptors (SRs) and other transcription factors (TFs), is an intricate web of signaling and functional processes that is still largely misunderstood at the mechanistic level. We are exploring the dynamic interplay between TFs with chromatin and the reprogramming of enhancer elements. We characterize the different modes of action of TFs in regulating enhancer activity, specifically, how different SRs target enhancer regions to reprogram chromatin in breast cancer cells. In addition, we have employed recent advances in live cell imaging technology to study the function of T factors in single cells in real time. Our approaches enable the coupling of population-based assays with real-time studies to address many unsolved questions about SRs and chromatin dynamics in breast cancer. 2. Cancer discovery has been focused primarily on the identification of critical mutated pathways, and the development of drugs to target the gene products of these so-called driver mutants. Critical driver mutants are not commonly identified, and therapies targeting these pathways are frequently followed by relapse. In fact, the regulatory networks that control global gene expression are massively transformed during cancer initiation and progression. The failure to normalize gene regulation and return cells to normal growth control is likely a major factor in treatment failure. To treat cancer effectively, a key issue is to identify the regulatory elements that create this abnormal expression pattern, rather than simply describing the gene expression pattern in tumor cells. Our primary goal is to analyze the status of enhancer networks in cancer cells, and identify enhancer signatures characteristic of progression and metastasis. Enhancer signatures predictive of cancer progression can then inform threat level for a specific tumor, appropriate patient therapy, and treatment progress for favorable response in enhancer status.
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