Phenotypic Consequences of Altered Regulation of Splicing Factors and microRNAs in Cancer

Cancer is a heterogeneous and complex disease, and alternative splicing and microRNAs have been implicated in cancer and cancer resistance to therapy. Investigating the regulators involved in tumorigenesis and mechanisms of resistance will help in our ability to better understand this disease and its treatments. Alterations in the levels of various splicing factors can result in disease-associated changes of splicing events. Our previous work discovered that splicing factors contribute to the development and maintenance of epithelial ovarian tumors and therapy resistance. Stemming from that, my study has revealed increased expression of two splicing factors, polypyrimidine tract-binding protein (PTBP1; PTB) and splicing factor, arginine/serine-rich 3 (SRSF3; SRp20), in breast cancers; these appear to be required for breast tumor cell growth and maintenance of transformation properties. These splicing factors, which seem to behave as oncogenes, may represent novel therapeutic targets for the treatment of some breast cancers and may play roles in therapy resistance. The acquisition of resistance to anticancer drugs is widely viewed as a key obstacle to successful cancer therapy. In light of altered microRNA expression studied extensively in human cancers and response to treatment, the aim of my study was to examine the involvement of microRNAs in drug-resistant cancer cells and to assess the possible associations between microRNAs and drug resistance. My data suggest that some microRNAs play a significant role in cellular responses to genotoxic agents and could be involved in the development of cancer drug resistance. Accordingly, targeting microRNA expression could be a potential approach to prevent or circumvent anticancer drug resistance. Indeed, using microRNA profiling, I uncovered a novel mechanism associated with HoxA9 expression and changes in specific microRNA expression by which leukemia cells survive chemotherapy and subsequently develop chemoresistance.