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Genes Dev. 2019 Feb 1;33(3-4):166-179. doi: 10.1101/gad.319889.118. Epub 2019 Jan 28.

CD44 splice isoform switching determines breast cancer stem cell state.

Author information

1
Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
2
Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
3
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
4
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
#
Contributed equally

Abstract

Although changes in alternative splicing have been observed in cancer, their functional contributions still remain largely unclear. Here we report that splice isoforms of the cancer stem cell (CSC) marker CD44 exhibit strikingly opposite functions in breast cancer. Bioinformatic annotation in patient breast cancer in The Cancer Genome Atlas (TCGA) database reveals that the CD44 standard splice isoform (CD44s) positively associates with the CSC gene signatures, whereas the CD44 variant splice isoforms (CD44v) exhibit an inverse association. We show that CD44s is the predominant isoform expressed in breast CSCs. Elimination of the CD44s isoform impairs CSC traits. Conversely, manipulating the splicing regulator ESRP1 to shift alternative splicing from CD44v to CD44s leads to an induction of CSC properties. We further demonstrate that CD44s activates the PDGFRβ/Stat3 cascade to promote CSC traits. These results reveal CD44 isoform specificity in CSC and non-CSC states and suggest that alternative splicing provides functional gene versatility that is essential for distinct cancer cell states and thus cancer phenotypes.

KEYWORDS:

CD44s; CSC; PDGFRβ/Stat3; alternative splicing; breast cancer

PMID:
30692202
PMCID:
PMC6362815
DOI:
10.1101/gad.319889.118
[Indexed for MEDLINE]
Free PMC Article

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