Thursday, April 25, 2024
4/25/2024
DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) is a serious health concern. Representing 10-20% of all breast cancers, TNBC is more aggressive than other forms of the disease, with a younger average age of diagnosis, increased rate of relapse, and decreased survival. One of the greatest challenges presented by TNBC is the lack of common oncogenic 'drivers' associated with the disease, thus limiting strategies for targeted therapeutics. Currently, there are no effective targeted therapies available to treat the disease, unlike other forms of breast cancer driven by estrogen receptor and HER2 in which treatment with tamoxifen and trastuzumab has made a substantial impact on survival. Profiling of a large number of TNBC tumors has identified a wide variety of low- frequency mutations, and our laboratory recently published a study showing that there are at least six distinct molecular subtypes of the disease. The long-term goals of our research are to identify pathways that can be therapeutically targeted in TNBC. One feature shared by a majority of TNBC cases is missense mutations in the gene encoding the p53 tumor suppressor (TP53), which result in the production of a non-functional version of the protein with a single amino acid difference. Recent studies have identified special "gain of function" properties conferred by some of these mutant proteins that enhance cell proliferation, migration and resistance to chemotherapeutic agents. Further, our laboratory has preliminary data showing growth inhibition of certain mutant-p53 cells after shRNA expression that decreases the levels of p53 RNA and protein, confirming previously published data. Based on these collective data, we hypothesize that tumors with p53 missense mutations exist in a mutant p53-adpated state, and determining the molecular underpinnings of this state will provide insight into targets for therapeutic development. In order to test this hypothesis, we propose three aims: 1) to determine mechanisms contributing to the mutant p53-adapted state, 2) to identify genes whose knockdown specifically inhibits p53-mutant TNBC cells, and 3) to develop missense mutant- specific molecular signatures through differential gene expression analysis of clinical tumor samples. We will leverage modern techniques including transcriptional analysis and whole-genome genetic screening across a wide array of cell lines and distinct p53 missense mutants. In addition, we will incorporate an ever-growing body of transcriptional and genomic datasets from publically available resources such as The Cancer Genome Atlas in order to identify molecular features associated with specific p53 missense mutants in the context of patient tumor samples. In the process, we will increase our understanding of how tumors adapt to mutant p53 and test our hypothesis that targeting this adapted state is a way to specifically inhibit cancer cells. The results generated from our studies will have potential translation to nearly every form of human cancer, and could help in the fight against TNBC as well as other diseases with high-frequency p53 mutation, such as ovarian cancer and lung squamous cell carcinoma, for which no effective targeted therapy has yet been found.
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