Project 2: Bromodomains as Epigenetic Modulators of Endocrine Responsiveness in ER+ Breast Cancer

点击翻译按钮获取中文摘要

PROJECT 2: SUMMARY Breast cancer (BCa) ranks among the leading causes of cancer death in women worldwide. Estrogen Receptor alpha positive tumors (ER+) are the most common subtype of BCa (~70% of all cases), and are effectively treated with anti-endocrine therapies that target ER. However, relapse frequently occurs resulting in the development of endocrine therapy resistance (ETR) and late stage metastatic disease. Substantial evidence indicates that transcriptional plasticity is a prominent feature of ETR, which provides subpopulations of cancer cells with the ability to adapt to therapeutic challenges. However, the molecular regulatory networks that govern anti-estrogen responsiveness in BCa cells remain poorly understood. It is well established that histone lysine acetylation patterns establish cell type enhancer programs to direct BCa phenotypes. Bromodomain (BRD) chromatin reader proteins are the primary readers of histone lysine acetylation. Despite being recognized as key epigenetic mechanisms in cancer and emerging `druggable targets', there are large gaps in our understanding of the functional relationships that exist between histone acetyllysine and BRDs. In addition, little is known regarding the role of BRDs in BCa anti-estrogen responses. We have previously characterized the altered epigenomic profiles in cell models of BCa and ETR. Our published results provide support that epigenome-wide reprogramming of estrogen-responsive elements is linked to endocrine sensitivity and the acquisition of ETR. Through an integrated and systematic set of specific aims, we will test the hypothesis that BRDs mediate endocrine responsiveness in BCa. This project will specifically focus on three main aspects that might have the potential for improved targeted therapies: The identification of specific bromodomain-containing proteins that can be targeted to enhance cellular responses to tamoxifen in cancer treatment, determination of the contributions of BRD-containing proteins to transcriptional plasticity during the early and late phases of ET, and characterization of the epigenetic landscape of recurrent metastatic ER+ breast cancer to link the global acetylome with histone binding activity of BRDs. Overall, this work will contribute to our understanding of BCa epigenetic mechanisms and will facilitate the discovery of new biomarkers for endocrine responsiveness and the development of new modalities for therapeutic intervention.