Treatment of breast cancer based on histological diagnosis and detection of molecular markers in cancer cells has been valuable in designing proper regimens for targeted therapy. Nevertheless, the clinical outcome remains uncertain due to the heterogeneity of tumor microenvironments and the genetic traits of individuals. Even though advanced sequencing technology has made it possible to profile an individual’s genome for personalized medicine, many cancer-driver genes and their expression patterns often exhibit an undetectable or minor difference between cancer and normal cells. This highlights the need for new diagnosis and prognosis strategies. Recently, two small compounds against the epi...

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Treatment of breast cancer based on histological diagnosis and detection of molecular markers in cancer cells has been valuable in designing proper regimens for targeted therapy. Nevertheless, the clinical outcome remains uncertain due to the heterogeneity of tumor microenvironments and the genetic traits of individuals. Even though advanced sequencing technology has made it possible to profile an individual’s genome for personalized medicine, many cancer-driver genes and their expression patterns often exhibit an undetectable or minor difference between cancer and normal cells. This highlights the need for new diagnosis and prognosis strategies. Recently, two small compounds against the epigenetic regulator BRD4 have shown promising anticancer effects in cultured cells and animal models associated with a subset of blood and solid (including breast) cancers. However, these compounds that globally inhibit BRD4 binding to chromatin also perturb normal cellular processes depending on BRD4-regulated gene activity in various cell lineages, thereby eliciting unwanted side effects in cancer therapy. To develop more selective targeted therapy, we conducted two large-scale compound library screens and identified 37 compounds that inhibit BRD4 function specifically through blocking its interaction with other pathway-specific regulators without shutting down the universal chromatin binding activity of BRD4. In this application, we will define the molecular action of these new compounds and examine their effects on suppressing breast cancer cell growth and migration using in vitro cell culture systems and in vivo mouse breast cancer models as well as patient-derived tumor samples. Moreover, we will conduct genome profiling of normal and breast cancer cells with or without compound treatment to identify gene targets and cellular pathways uniquely regulated by these new compounds with distinct modes of action compared to the chromatin-binding inhibitors of BRD4.

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