Mechanisms of Noncoding Enhancer RNA Function in Triple-Negative Breast Cancer
Abstract
The classification of the molecular subtypes of breast tumors using expression profiling is perhaps one of the most important triumphs of genomic profiling in tumors since the provision of the human genome sequence in 2001. Using histologic analysis together with genetic profiling, scientists and clinicians are able to classify breast tumors according to the combination of proteins being expressed in the tumors. This classification has had great implications in the diagnosis, prognosis, and treatment regimens for patients. However, despite out best efforts, breast cancer remains the second leading cause of cancer mortality in women. With the ever-increasing feasibility of next-generation sequencing technologies, we have learned that our genomes are dynamic and contain the information for the production of many other molecules, not just proteins. One such class of molecules that cancer biologists are now beginning to understand is called enhancer RNAs (eRNAs). These enhancer RNAs are produced from regulatory regions of the genome, called enhancers, and are aberrantly expressed in human cancers. In breast cancer, regulatory regions of the genome are hijacked by the tumor cells for the activation of oncogenes that lead to cancer initiation and progression. In addition, the regulatory regions of the genome are repurposed by the tumor cells for the up-regulation of genes that allow tumor cells to become resistant to therapy. It is hypothesized that the eRNAs produced from these regulatory regions are likely to contribute to these mechanisms. We believe that eRNAs and the enhancers from which they are produced have the potential to completely change the way we think about cancer biology because a few pioneer studies have shown that eRNAs are involved in gene expression and can dictate when and where certain genes are turned on and off. Therefore, improper eRNA function can lead to uncontrolled gene expression, allowing cells to escape regulated cell growth, leading to cancer initiation and progression. Thus, the studies proposed herein will help address the overarching challenge of identifying what drives breast cancer growth and determine how to stop it. This proposal addresses how genetic information encoded in the genome as eRNAs can direct the cellular proliferation program in triple-negative breast cancer cells. Using a new genomic profiling technique, we have identified hundreds of new eRNAs that are aberrantly expressed in triple-negative breast cancer and whose function are not known. We intend to study these eRNAs, the enhancers from which they originate, and their target genes using an interdisciplinary approach that involves the development and use of: (1) state-of-the-art genomic approaches coupled with novel bioinformatic and computational strategies, (2) high-throughput screens to analyze the target genes of eRNAs in single cells, and (3) a study on the biological consequences of eRNA perturbation in breast cancer mouse models and primary tumor samples. Our broad screens will be complemented by a set of focused, gene-specific, molecular analyses that have the potential to uncover and reveal new mechanistic insights. The potential clinical applications and benefits of studying eRNA function lies in the ability to use eRNAs and the genes they regulate as biomarkers for treatment, and also for possible therapies by targeting the eRNAs themselves or targeting the eRNA-DNA or eRNA-protein interactions that mediate their function. Therefore, the studies outlined in this proposal will accomplish four important goals: (1) increase our knowledge about a new fact of breast cancer that is largely unexplored (eRNAs), (2) advance the way that breast cancer research is conducted, (3) provide a new set of markers with great diagnostic and prognostic potential, and (4) provide a new set of targets for controlling breast cancer cell growth, which have therapeutic potential. As such, the proposed studies have
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910049
Entities
People
- Hector Franco
Organizations
- United States Army
- University of North Carolina at Chapel Hill