A Novel Isoform of CPEB2 Regulates the Metastasis of Triple Negative Breast Cancer

Abstract

While breast cancer has an overall 5‐year survival rate of 90%, triple negative breast cancer (TNBC) represents an anomalous subset of the disease with a greatly reduced (30%) 5‐year survival rate. The enhanced mortality and morbidity associated with TNBC arises from the high metastatic rate, which requires the acquisition of anoikis resistance (AnR). As the dysregulation of mRNA splicing is becoming a recognized phenomenon in cancer and aberrant cell signaling, the alternative mRNA splicing events were interrogated in AnR TNBC cells using next generation sequencing. The mRNA splicing of cytoplasmic polyadenylation element binding 2 (CPEB2), a translational regulator, was identified as dysregulated in AnR TNBC. Specifically, the inclusion of exon 4 into the mature mRNA to produce high levels of the CEPB2B isoform correlated with AnR, which translated to human breast cancer tumors. Furthermore, the molecular manipulation of CPEB2 isoforms had a robust effect on AnR and the metastatic potential of TNBC. Finally, next generation sequencing indicated a subset of mRNA species related to both tumor suppression and oncogenesis were differentially regulated by specific CPEB2 splice variants. Overall, our findings demonstrate that the regulation of CPEB2 mRNA splicing is a key step in the acquisition of AnR for TNBC as well as a major driving force in metastasis.