An emt-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype

Irina M. Shapiro, Albert W. Cheng, Nicholas C. Flytzanis, Michele Balsamo, John S. Condeelis, Maja H. Oktay, Christopher B. Burge, Frank B. Gertler

Research output: Contribution to journalArticle

241 Citations (Scopus)

Abstract

Epithelial-mesenchymal transition (EMT), a mechanism important for embryonic development, plays a critical role during malignant transformation. While much is known about transcriptional regulation of EMT, alternative splicing of several genes has also been correlated with EMT progression, but the extent of splicing changes and their contributions to the morphological conversion accompanying EMT have not been investigated comprehensively. Using an established cell culture model and RNA-Seq analyses, we determined an alternative splicing signature for EMT. Genes encoding key drivers of EMT-dependent changes in cell phenotype, such as actin cytoskeleton remodeling, regulation of cell-cell junction formation, and regulation of cell migration, were enriched among EMT-associated alternatively splicing events. Our analysis suggested that most EMT-associated alternative splicing events are regulated by one or more members of the RBFOX, MBNL, CELF, hnRNP, or ESRP classes of splicing factors. The EMT alternative splicing signature was confirmed in human breast cancer cell lines, which could be classified into basal and luminal subtypes based exclusively on their EMT-associated splicing pattern. Expression of EMT-associated alternative mRNA transcripts was also observed in primary breast cancer samples, indicating that EMT-dependent splicing changes occur commonly in human tumors. The functional significance of EMT-associated alternative splicing was tested by expression of the epithelial-specific splicing factor ESRP1 or by depletion of RBFOX2 in mesenchymal cells, both of which elicited significant changes in cell morphology and motility towards an epithelial phenotype, suggesting that splicing regulation alone can drive critical aspects of EMT-associated phenotypic changes. The molecular description obtained here may aid in the development of new diagnostic and prognostic markers for analysis of breast cancer progression.

Original languageEnglish (US)
Article numbere1002218
JournalPLoS Genetics
Volume7
Issue number8
DOIs
StatePublished - Aug 2011

Fingerprint

Epithelial-Mesenchymal Transition
alternative splicing
Alternative Splicing
breast neoplasms
phenotype
cancer
Breast Neoplasms
Phenotype
gene
cells
intercellular junctions
embryonic development
motility
development aid
tumor
RNA
microfilaments
cell movement
cell culture
embryogenesis

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

An emt-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. / Shapiro, Irina M.; Cheng, Albert W.; Flytzanis, Nicholas C.; Balsamo, Michele; Condeelis, John S.; Oktay, Maja H.; Burge, Christopher B.; Gertler, Frank B.

In: PLoS Genetics, Vol. 7, No. 8, e1002218, 08.2011.

Research output: Contribution to journalArticle

Shapiro, Irina M. ; Cheng, Albert W. ; Flytzanis, Nicholas C. ; Balsamo, Michele ; Condeelis, John S. ; Oktay, Maja H. ; Burge, Christopher B. ; Gertler, Frank B. / An emt-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. In: PLoS Genetics. 2011 ; Vol. 7, No. 8.
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