Deregulation of alternative splicing (AS) has been implicated in the development of drug resistance, tumor progression and metastasis. RNA-binding proteins (RBPs) as controllers of AS may act as master regulators of cellular behavior. Among the RBPs, we previously have shown that the expression of epithelial splicing regulatory proteins 1 and 2 (ESRP1 & ESRP2) have significantly elevated in cases with high Oncotype DX scores and in ERα-positive cells with acquired tamoxifen resistance (MCF-7/ LCC2) (SABCS 2013). This study seeks to identify genes and their splice variants that are regulated by ESRP1 & ESRP2 and could cause development of endocrine resistance. To identify alternatively spliced genes by ESRP1 & ESRP2 in endocrine resistance, we have performed a four step bioinformatics approach as follows: 1) Motif analysis to identify genes targeted by ESRP1 & ESRP2, 2) Comparison of differentially expressed genes in tamoxifen treated samples (GSE17700 and GSE17705) with genes targeted by ESRP1 & ESRP2 identified above, 3) Protein-protein interaction from BIOGRID and 4) survival data using publically available datasets (KM Plotter). Motif analysis identified 15,450 genes targeted both by ESRP1 (P<3.39e-05) and ESRP2 (P< 5.53e-05). 2212 of these genes were differentially expressed in tamoxifen treated cases. This set of genes was further categorized based on the ESRP1 & ESRP2 enhancer/ suppressor motifs ratio resulting in 1260 genes. Further collective analysis of survival data from KM plotter (P<0.001) and number of protein-protein interactions (>50) narrowed down 79 candidate genes that are associated with tamoxifen resistance. Some of the genes (AURKA, ERRB3, ESR2, EGFR, and MDM2) have been previously implicated in the de novo or acquired resistance to tamoxifen. Validation of splicing variants of these genes in human tumors is ongoing. Elevated expression of ESRP1 & ESRP2 and its target genes play an important role in the development of tamoxifen resistance and recurrence of ER+ breast cancer. ESRP1 & ESRP2 by affecting splicing have the potential to induce tamoxifen resistance via multiple genes and pathways. Targeting ESRP1 & ESRP2 may offer novel avenues for combating endocrine-resistance in breast cancer.

Citation Format: Yesim Gokmen-Polar, Yaseswini Nellamraju, Xiaoping Gu, Sarath C. Janga, Sunil S. Badve. Splicing factors ESRP1/ESRP2 as regulators of endocrine resistance in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4187. doi:10.1158/1538-7445.AM2014-4187