Myc Regulates Alternative Splicing Through A Network Of Rna Binding Proteins In Breast Cancer

The oncogenic transcription factor MYC is one of the most frequently altered genes in cancer and is highly dysregulated in aggressive tumor types, including triple negative breast cancer (TNBC). Although direct targeting of MYC or its regulators in human tumors has proved difficult, the undisputed clinical relevance of this transcription factor warrants continued study for therapeutic targeting of MYC-driven processes in tumors. Recently, we and others have shown the tumorigenic capacity of MYC is critically dependent on the RNA splicing machinery and on several splicing factor RNA-binding proteins (RBPs). Dysregulation of alternative mRNA splicing, a key step in gene expression regulation, is a hallmark of cancer, and can lead to the expression of isoforms driving tumor initiation, progression or drug resistance. Understanding which component(s) of the RNA machinery are regulated by MYC, and the functions of MYC-induced spliced isoforms, may reveal new targets that circumvent prior failures of directly targeting MYC. Here, we examine MYC-induced changes in gene expression and alternative splicing through RNA-sequencing of breast cell lines and tumors. Using a mammary epithelial cell line with an inducible MYC system, we identified over 4,000 MYC-induced alternative splicing events as well as 378 MYC-induced RBPs. Co-expression network analysis of these RBPs in TCGA breast tumor RNA-seq data uncovered 8 RBP modules, four of which are highly correlated with MYC activity and highly expressed in TNBC. One of these modules is preserved across almost all other TCGA tumor types and remains highly correlated with MYC activity, suggesting a pan-cancer role of this co-expression module. We are now defining the functional role of these RBP modules in MYC-driven tumorigenesis in breast cancer models, as well as identifying their downstream oncogenic splicing targets. Our research project will define the role and regulation of alternative splicing in breast cancer, and more specifically in aggressive tumor types such as TNBC. Our findings will provide mechanistic insight into the role of MYC-driven splicing in tumor maintenance and will uncover novel therapeutic targets for MYC-active tumors. Citation Format: Laura Urbanski, Brittany Angarola, Mattia Brugiolo, Marina Yurieva, Sunghee Park, Olga Anczukow. Myc regulates alternative splicing through a network of RNA binding proteins in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-07.