SRSF1-Regulated Alternative Splicing in Breast Cancer

Mol Cell. 2015 Oct 1;60(1):105-17. doi: 10.1016/j.molcel.2015.09.005.


Splicing factor SRSF1 is upregulated in human breast tumors, and its overexpression promotes transformation of mammary cells. Using RNA-seq, we identified SRSF1-regulated alternative splicing (AS) targets in organotypic three-dimensional MCF-10A cell cultures that mimic a context relevant to breast cancer. We identified and validated hundreds of endogenous SRSF1-regulated AS events. De novo discovery of the SRSF1 binding motif reconciled discrepancies in previous motif analyses. Using a Bayesian model, we determined positional effects of SRSF1 binding on cassette exons: binding close to the 5' splice site generally promoted exon inclusion, whereas binding near the 3' splice site promoted either exon skipping or inclusion. Finally, we identified SRSF1-regulated AS events deregulated in human tumors; overexpressing one such isoform, exon-9-included CASC4, increased acinar size and proliferation, and decreased apoptosis, partially recapitulating SRSF1's oncogenic effects. Thus, we uncovered SRSF1 positive and negative regulatory mechanisms, and oncogenic AS events that represent potential targets for therapeutics development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Bayes Theorem
  • Binding Sites
  • Breast Neoplasms / genetics*
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks*
  • HeLa Cells
  • Humans
  • Mutation
  • RNA Splice Sites
  • Sequence Analysis, RNA / methods*
  • Serine-Arginine Splicing Factors / chemistry*
  • Serine-Arginine Splicing Factors / genetics
  • Serine-Arginine Splicing Factors / metabolism*


  • RNA Splice Sites
  • SRSF1 protein, human
  • Serine-Arginine Splicing Factors

Associated data

  • SRA/SRP062609