Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 121, Issue 3, Pages 1064-1074Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI44540
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Funding
- NCI [CCSG P30 CA60553]
- American Cancer Society
- American Association for Cancer Research
- Schweppe Foundation
- NIH [T32-CA009560-21]
- Department of Defense
- Northwestern University
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Epithelial-mesenchymal transition (EMT) is a tightly regulated process that is critical for embryogenesis but is abnormally activated during cancer metastasis and recurrence. Here we show that a switch in CD44 alternative splicing is required for EMT. Using both in vitro and in vivo systems, we have demonstrated a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) during EMT. This isoform switch to CD44s was essential for cells to undergo EMT and was required for the formation of breast tumors that display EMT characteristics in mice. Mechanistically, the splicing factor epithelial splicing regulatory protein 1 (ESRP1) controlled the CD44 isoforrn switch and was critical for regulating the EMT phenotype. Additionally, the CD44s isoform activated Akt signaling, providing a mechanistic link to a key pathway that drives EMT. Finally, CD44s expression was upregulated in high-grade human breast tumors and was correlated with the level of the mesenchymal marker N-caciherin in these tumors. Together, our data suggest that regulation of CD44 alternative splicing causally contributes to EMT and breast cancer progression.
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