Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways

Yesim Gökmen-Polar, Yaseswini Neelamraju, Chirayu P. Goswami, Yuan Gu, Xiaoping Gu, Gouthami Nallamothu, Edyta Vieth, Sarath C. Janga, Michael Ryan, Sunil S. Badve

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Article numbere46078
JournalEMBO Reports
Volume20
Issue number2
DOIs
StatePublished - Feb 1 2019

Keywords

  • ER-positive breast cancer
  • ESRP1
  • HTA
  • alternative splicing
  • fatty acid metabolism

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Gökmen-Polar, Y., Neelamraju, Y., Goswami, C. P., Gu, Y., Gu, X., Nallamothu, G., Vieth, E., Janga, S. C., Ryan, M., & Badve, S. S. (2019). Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways. EMBO Reports, 20(2), [e46078]. https://doi.org/10.15252/embr.201846078