COMPREHENSIVE FUNCTIONAL AND MOLECULAR PROFILING AND INTEGRATIVE ANALYSES OF PRIMARY AND METASTATIC TRIPLE NEGATIVE BREAST CANCERS

Abstract

In summary, the first project was focused on investigating inter/intra-tumor epigenetic heterogeneity in TNBCs and its functional relevance. We characterized the heterogeneity of TNBCs, by combining functional and molecular profiling with computational tools. We defined transcriptional, epigenetic and metabolomic subtypes and identified subtype-driving super-enhancers. Furthermore, we found that the mesenchymal TNBC is more similar to the mesenchymal neuroblastoma and rhabdoid tumors than the other TNBC subtypes, and we identified that PRRX1 transcription factor as a key driver of these tumors. Lastly, single cell analyses revealed relative homogeneity of the three major transcriptional subtypes within the tumors. The second project was focused on performing integrative analyses using a multi-level biomarker association approach to evaluate variations between the biomarkers. This study’s findings provide new insights into utility of different markers and suggest alternative way to measure TNBC heterogeneity. Overall, this thesis will provide deeper understanding of epigenetic-based regulation of TNBC heterogeneity, it will enable to us to explore, identify, and test novel targets and help us improve methods to measure the heterogeneity. Both projects presented herein have high clinical and scientific merit.