Inflammation is known to have a paradoxical effect on cancers being able to both promote and inhibit the growth of tumors. It is known that crosstalk between the endocrine and immune systems play key roles in determining the phenotypes and outcomes of hormone dependent cancers such as breast cancer. The studies outlined in this proposal are poised to determine how the estrogen and proinflammatory signaling pathways converge in cancer cells to regulate the expression of many genes important for initiation, growth and metastasis. The responses of cancer cells to estrogens and proinflammatory signaling molecules are largely mediated by DNA binding proteins, known as transcription factors, that bind to regulatory regions of the genome to change the expression of many target genes. More specifically, this study will focus the inflammatory-mediated mechanisms that influence the function of the pioneer transcription factor FoxA1. The preliminary data for this research proposal shows that proinflammatory signaling, in cooperation with estrogen signaling, causes FoxA1 to bind to regions of the genome that were thought to be dormant or latent in breast cancer cells. This, in turn, activates the expression of a novel set of genes that are stron predictors of clinical outcomes in breast cancer patients. This work is significant because it provides a framework for the integration of two of the major signaling cascades that exacerbate tumorigenesis. The applicant will use state-of-the-art molecular biology, genomic and proteomic methodologies in both cell-based and mouse models of breast cancer, to address the aims of this study. This integrated approach will allow for systematic analysis of FoxA1 function, and the downstream consequences, during proinflammatory signaling in breast cancer. The goal of the applicant is to use the academic, research and leadership training received during the tenure of this award to successfully transition into an independent tenure track faculty position. As the principal investigator of a competitive research group at a major university or medical center, the motivation for the science being done in the applicant's laboratory will be to discover new avenues for the prevention and treatment of cancer by understanding how gene regulation and cell signaling influence cancer biology. To date, the applicant's research demonstrates an aptitude for molecular biology, biochemistry and next-generation sequencing technologies and the goal for the mentored phase of training is to gain experience with the use of proteomics and animal models. UT Southwestern Medical Center is an idea location for completion of the mentored phase because it is a research-oriented university that provides an exceptional and highly interactive scientific and intellectual environment. UT Southwestern's research faculty include 18 members of the National Academy of Sciences, 13 members of the Howard Hughes Medical Institute, and five Nobel Laureates. Frequent interactions with the candidate's primary mentor and advisory committee will continue to develop the research techniques, scientific knowledge and leadership skills needed to transition into an independent career.
Recent studies have highlighted the multitudinous avenues for crosstalk between the immune system and the endocrine system in cancer. It is known that inflammation is important for the development, progression and response to treatment of many cancers, and, in breast cancer, is known to play a key role in the development of resistance to hormone therapy. Therefore, this proposal is poised to define the molecular mechanisms that govern gene expression outcomes, and ultimately phenotypical outcomes, of cancer cells exposed to inflammatory and hormone signaling.
| Franco, Hector L; Nagari, Anusha; Malladi, Venkat S et al. (2018) Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis. Genome Res 28:159-170 |
