Identification of spliceosome components pivotal to breast cancer survival

Abstract

Cancer cells employ alternative splicing (AS) to acquire splicing isoforms favouring their survival. However, the causes of aberrant AS in breast cancer are poorly understood. In this study, the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) data were analysed with univariate feature selection. Of 122 analysed spliceosome components, <i>U2SURP, PUF60, DDX41, HNRNPAB, EIF4A3</i>, and <i>PPIL3</i> were significantly associated with breast cancer survival. The top 4 four genes, <i>U2SURP, PUF60, DDX41</i>, and <i>HNRNPAB</i>, were chosen for further analyses. Their expression was significantly associated with cancer molecular subtype, tumour stage, tumour grade, overall survival (OS), and cancer-specific survival in the METABRIC data. These results were verifiable using other cohorts. The Cancer Genome Atlas data unveiled the elevated expression of <i>PUF60, DDX41</i>, and <i>HNRNPAB</i> in tumours compared with the normal tissue and confirmed the differential expression of the four genes among cancer molecular subtypes, as well as the associations of <i>U2SURP, PUF60</i>, and <i>DDX41</i> expression with tumour stage. A meta-analysis data verified the associations of <i>U2SURP, PUF60</i>, and <i>HNRNPAB</i> expression with tumour grade, the associations of <i>PUF60, DDX41</i>, and <i>HNRNPAB</i> expression with OS and distant metastasis-free survival, and the associations of <i>U2SURP</i> and <i>HNRNPAB</i> expression with relapse-free survival. Experimentally, we demonstrated that inhibiting the expression of the four genes separately suppressed cell colony formation and slowed down cell growth considerably in breast cancer cells, but not in immortal breast epithelial cells. In conclusion, we have identified <i>U2SURP, PUF60, DDX41</i>, and <i>HNRNPAB</i> are spliceosome-related genes pivotal for breast cancer survival.