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

doi:10.15252/embr.201846078

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

EMBO Rep. 2019 Feb;20(2):e46078. doi: 10.15252/embr.201846078. Epub 2019 Jan 21.

Authors

Yesim Gökmen-Polar¹, Yaseswini Neelamraju², Chirayu P Goswami³, Yuan Gu⁴, Xiaoping Gu⁴, Gouthami Nallamothu⁴, Edyta Vieth⁴, Sarath C Janga^{5

6

7}, Michael Ryan^{8

9}, Sunil S Badve^{1

10

11}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA ypolar@iu.edu sbadve@iupui.edu.
² Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
³ Department of Bioinformatics, Thomas Jefferson University Hospitals, Philadelphia, PA, USA.
⁴ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Department of BioHealth Informatics, School of Informatics and Computing, IUPUI, Indianapolis, IN, USA.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁷ Centre for Computational Biology and Bioinformatics Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ In Silico Solutions, Falls Church, VA, USA.
¹⁰ Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
¹¹ Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

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.

Keywords: ESRP1; HTA; ER‐positive breast cancer; alternative splicing; fatty acid metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing
Antineoplastic Agents / pharmacology
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Energy Metabolism*
Epithelial-Mesenchymal Transition / genetics
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Metabolic Networks and Pathways*
Proportional Hazards Models
RNA Splicing Factors / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Receptors, Estrogen / metabolism*

Substances

Antineoplastic Agents
ESRP1 protein, human
RNA Splicing Factors
RNA-Binding Proteins
Receptors, Estrogen

Grants and funding

R01 GM123314/GM/NIGMS NIH HHS/United States