Hypoxia-induced molecular alterations and druggable targets in triple negative breast cancer cell lines - HipTNBC

Despite advances in the treatment of triple negative breast cancer (TNBC), the outcomes for many patients remain suboptimal due to tumour heterogeneity. One of the factors contributing to the heterogeneity in TNBC is hypoxia. Hypoxia-associated alterations depend on the pattern of hypoxic exposure. To achieve better outcomes, it is crucial to identify specific molecular alterations induced by various types of hypoxia. The aim of the proposed research is to identify and to verify molecular alterations and druggable targets associated with acute, cycling and chronic hypoxia in TNBC. Hypoxia-induced molecular alterations (somatic genomic alterations; mRNA, miRNA, protein expression and DNA methylation) and druggable targets (e.g., BH3 mimetics) based on mitochondrial apoptotic dependencies in TNBC will be identified by bioinformatics analysis of publicly available multi-omics data sets, using hypoxia-related mRNA signatures. Molecular alterations and druggable targets identified during this and baseline BH3 profiling analysis will be validated in TNBC reference cell lines exposed to acute hypoxia, cycling hypoxia and chronic hypoxia. The outcomes of this research will be potential tumour-hypoxia related indicators and list of potential therapeutic agents for development of personalized therapy field. In a long-term perspective, the project will contribute to improvements in the management, survival and health-related quality of life of TNBC patients.