Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer

SIMPLE SUMMARY: The alternative splicing (AS) process is highly relevant, affecting most of the hallmarks of cancer, such as proliferation, angiogenesis, and metastasis. Our study evaluated alterations in 304 splicing-related genes and their prognosis value in breast cancer patients. Amplifications in CLNS1A, LSM1, and ILF2 genes in luminal patients were significantly associated with poor outcome. Downregulation of these genes in luminal cell lines showed an antiproliferative effect. Pharmacological modulation of transcription and RNA regulation is key for the optimal development of therapeutic strategies against key proteins. Administration of a BET inhibitor and BET-PROTAC reduced the expression of these identified genes and displayed a significant antiproliferative effect on these cell models. In conclusion, we describe novel splicing genes amplified in luminal breast tumors that are associated with detrimental prognosis and can be modulated pharmacologically. It opens the door for further studies confirming the effect of these genes in patients treated with BET inhibitors. ABSTRACT: Alternative splicing is an essential biological process, which increases the diversity and complexity of the human transcriptome. In our study, 304 splicing pathway-related genes were evaluated in tumors from breast cancer patients (TCGA dataset). A high number of alterations were detected, including mutations and copy number alterations (CNAs), although mutations were less frequently present compared with CNAs. In the four molecular subtypes, 14 common splice genes showed high level amplification in >5% of patients. Certain genes were only amplified in specific breast cancer subtypes. Most altered genes in each molecular subtype clustered to a few chromosomal regions. In the Luminal subtype, amplifications of LSM1, CLNS1A, and ILF2 showed a strong significant association with prognosis. An even more robust association with OS and RFS was observed when expression of these three genes was combined. Inhibition of LSM1, CLNS1A, and ILF2, using siRNA in MCF7 and T47D cells, showed a decrease in cell proliferation. The mRNA expression of these genes was reduced by treatment with BET inhibitors, a family of epigenetic modulators. We map the presence of splicing-related genes in breast cancer, describing three novel genes, LSM1, CLNS1A, and ILF2, that have an oncogenic role and can be modulated with BET inhibitors.