CD44 splice isoform switching determines breast cancer stem cell state.

TitleCD44 splice isoform switching determines breast cancer stem cell state.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhang, H, Brown, RL, Wei, Y, Zhao, P, Liu, S, Liu, X, Deng, Y, Hu, X, Zhang, J, Gao, XD, Kang, Y, Mercurio, AM, Goel, HLal, Cheng, C
JournalGenes Dev
Volume33
Issue3-4
Pagination166-179
Date Published2019 02 01
ISSN1549-5477
KeywordsAlternative Splicing, Animals, Breast Neoplasms, Cell Line, Tumor, Disease Models, Animal, Female, Gene Expression Regulation, Neoplastic, Humans, Hyaluronan Receptors, Mice, Neoplastic Stem Cells, Protein Isoforms, Signal Transduction
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.

DOI10.1101/gad.319889.118
Alternate JournalGenes Dev.
PubMed ID30692202
PubMed Central IDPMC6362815
Grant ListR01 CA182467 / CA / NCI NIH HHS / United States
R01 CA203439 / CA / NCI NIH HHS / United States
R01 GM110146 / GM / NIGMS NIH HHS / United States
T32 CA080621 / CA / NCI NIH HHS / United States