Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer
A Synthetic lethal (SL) interaction involves a pair of genes (geneA and geneB) where inhibition of either geneA or geneB individually has no effect on cell viability, but the inhibition of both geneA and geneB causes cell death. SL interactions that occur between gene pairs can be exploited for cancer therapeutics. Studies in the model eukaryote yeast have identified approximately 550,000 negative genetic interactions that have been extensively applied to characterize novel pathways and gene functions. In the context of this thesis, a negative genetic interaction is the equivalent of a SL interaction. Harnessing the vast available knowledge of yeast genetics, we generated a Humanized Yeast Genetic Interaction Network (HYGIN) for 1,009 human genes with yeast orthologs and 10,419 interactions. Through the addition of patient-data from The Cancer Genome Atlas (TCGA), we generated a breast cancer specific subnetwork. Specifically, by comparing 1,009 genes in HYGIN to genes that were down-regulated in breast cancer, we identified 15 breast cancer genes with 130 potential SL interactions. Interestingly, 32 of the 130 predicted SL interactions occurred with FBXW7, a well-known tumor suppressor that functions as a substrate-recognition protein within the SKP/CUL1/F-Box ubiquitin ligase complex for degradation through the proteasome. Validation of these SL interactions using chemical genetic data indicate that patients with loss of FBXW7 may respond to treatment with drugs like Selumitinib or Cabozantinib. Taken together, our patient-data driven interpretation of HYGIN represents a novel strategy to uncover therapeutically relevant drug targets.
Breast Cancer, Synthetic Lethality, Genetic Interactions
Master of Science (M.Sc.)