Unraveling the Impact of Aberrant Splicing Machinery on Drug Resistance in Breast Cancer: Identifying Targets for Innovative Counteractive Strategies

The alternative splicing of pre-mRNA is an important process that increases the number of proteins a genome can code for and is important for nearly all biological processes within a cell. Alternative splicing has been found to be dysregulated in cancers including breast cancer, where it contributes to the development and progression of the disease. Alternative splicing can also contribute to the development of drug resistance. This is due to either new isoform not being targeted by drugs or being able to bypass the inhibitory activity of drugs. These splicing events can alter the expression of proteins targeted by drugs, alter the expression of proteins involved in signaling pathways up or downstream of drug targets or they can occur in the components of the splicing machinery, resulting in broad changes in splicing of many other proteins. This can change the whole splicing pattern of a cell. This has resulted in alternative splicing becoming a viable target in the attempt to reverse drug resistance by targeting the new isoforms that can result in drug resistance. This can be done by targeting the mRNA coding for these new isoforms, targeting the pre-mRNA to correct or alter splicing, and targeting the protein isoforms through small molecular inhibitors that can bind to or specially act upon certain isoforms. Finally, the splicing machinery and splicing factors can be targeted in order to prevent the switch to pro-oncogenic splice variants. This chapter will explore the different splicing events that occur in individual genes, components of signaling pathways, or components of the splicing machinery, which can result in breast cancer developing resistance to specific treatments. It will then discuss mechanisms and strategies for targeting these transcripts, proteins, and regulators of splicing in order to switch splicing to favor the expression of anti, or non- carcinogenic splice variants.