Project 458336

Cancer is a leading cause of death worldwide across all demographics. In cancer, there is a "loss of control" (i.e., dysregulation) of genes essential for regulating cell growth. MYC is a protein that lies at the crossroads of many growth-signalling pathways and its dysregulation is linked to >50% of all human cancers. Developing drugs to inhibit MYC would revolutionize cancer treatments; however, efforts to target the protein directly have failed. One alternative approach is to identify and inhibit proteins that cells with dysregulated MYC depend on for survival. Inhibiting these would selectively kill MYC-driven cancer cells while sparing normal cells. To this end, we recently performed experiments on breast cancer cells to identify these proteins. Interestingly, we found that many of them regulated R-loops which are DNA:RNA hybrid structures that can form during transcription and when unregulated, are known to increase genomic instability. This finding suggests that tumours with deregulated MYC critically depend on R-loop regulators for cancer cell survival. Topoisomerase I (TOP1), a protein that has functions in regulating the formation of R-loops, was identified as a synthetic-lethal protein of interest because it is 1) potentially a MYC interactor and 2) druggable by clinical inhibitors. MYC, R-loops, and TOP1 all have critical functions in regulating transcription; however, how they work together remains unknown. To this end, I hypothesize that dysregulated MYC directly increases R-loop formation and therefore, cancer cells with deregulated MYC are critically dependent on R-loop regulators such as TOP1 for survival. If my hypothesis is accepted, this knowledge may translate to the clinic by providing the means to identify which breast cancers would be vulnerable to TOP1 drug inhibitors, thus improving resource distribution and patient quality-of-care.