Abstract 1737 Characterizing and targeting splicing-factor regulatory networks in aging and cancer

Upregulation of SR proteins, a family of 14 essential splicing factors (SFs), often occurs in solid tumors, including in breast, and promotes mammary cell transformation and metastasis in breast cancer models. SR protein alterations often occur without genomic copy number changes, suggesting misregulation at the transcriptional or post-transcriptional levels; however the underlying molecular mechanisms are incompletely understood. Here we investigate the transcriptional and post-transcriptional regulatory mechanisms that control SF-levels in normal mammary cells and their misregulation in cancer cells. We demonstrate the MYC oncogene directly regulates a network of splicing factors that are co-expressed in tumors and act together to regulate their downstream targets and promote cell invasion. In parallel, our work reveals the role of non-coding 'poison exon' in regulating SR proteins levels during cell differentiation and in tumors. We uncover an extensive cross-regulatory network used by the SR protein family to control their expression. Finally, we develop splice-switching antisense oligonucleotides to reverse the increased skipping of TRA2β poison exon detected in tumors, leading to selective anti-proliferative effects across a variety of cancer models. In summary, our work provides new insights into the regulatory mechanisms of SR proteins and identifies novel oncogenic spliced isoforms that represent potential biomarkers and targets for therapeutics development. This work was supported by NIH grants R01 GM138541, R01CA248317, P30 CA034196, T32AG062409A, the V foundation, and The Jackson Laboratory Start-Up funds.