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Splicing factor <scp>ESRP</scp> 1 controls <scp>ER</scp> ‐positive breast cancer by altering metabolic pathways

Authors :
Sarath Chandra Janga
Yaseswini Neelamraju
Xiaoping Gu
Edyta Vieth
Sunil Badve
Yuan Gu
Gouthami Nallamothu
Yesim Gökmen-Polar
Chirayu P. Goswami
Michael Ryan
Source :
EMBO reports. 20
Publication Year :
2019
Publisher :
EMBO, 2019.

Abstract

The epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) control the epithelial-to-mesenchymal transition (EMT) splicing program in cancer. However, their role in breast cancer recurrence is unclear. In this study, we report that high levels of ESRP1, but not ESRP2, are associated with poor prognosis in estrogen receptor positive (ER+) breast tumors. Knockdown of ESRP1 in endocrine-resistant breast cancer models decreases growth significantly and alters the EMT splicing signature, which we confirm using TCGA SpliceSeq data of ER+ BRCA tumors. However, these changes are not accompanied by the development of a mesenchymal phenotype or a change in key EMT-transcription factors. In tamoxifen-resistant cells, knockdown of ESRP1 affects lipid metabolism and oxidoreductase processes, resulting in the decreased expression of fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and phosphoglycerate dehydrogenase (PHGDH) at both the mRNA and protein levels. Furthermore, ESRP1 knockdown increases the basal respiration and spare respiration capacity. This study reports a novel role for ESRP1 that could form the basis for the prevention of tamoxifen resistance in ER+ breast cancer.

Details

ISSN :
14693178 and 1469221X
Volume :
20
Database :
OpenAIRE
Journal :
EMBO reports
Accession number :
edsair.doi...........906e7fae122bde8923902e019e9d1fba