An ERRα-ZEB1 transcriptional signature predicts survival in triple-negative breast cancers

Sep 22, 2026

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Transcription factors work with co-regulators to shape target-gene expression and thereby drive pathophysiological effects. ERRα is a transcription factor with diverse cancer-relevant activities, yet the co-activators responsible for its tumor-promoting, metabolism-independent functions in triple-negative breast cancer remain unclear. Bio-computing identified a candidate ERRα co-factor, and qPCR, ChIP, and proximity ligation assays validated ERRα co-regulation in TNBC cells. The resulting downstream gene signature predicts TNBC patient survival.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Background

Transcription factors and co-regulators

ERRα (ESRRA) and its metabolic role

Methods

Bio-computing to identify ERRα co-factors

Experimental validation in TNBC cells

Results

ZEB1 as a major ERRα co-factor

ERRα-ZEB1 signature predicts TNBC survival

Conclusions

Gene signature as a prognostic marker

Shi et al. Molecular Medicine (2026) 32:99 Molecular Medicine [https://doi.org/10.1186/s10020-026-01487-4](https://doi.org/10.1186/s10020-026-01487-4) RESEARCH Open Access An ERRα-ZEB1 transcriptional signature predicts survival in triple-negative breast cancers Jing-Ru Shi 1,2,3, Coralie Poulard3, Catherine Cerutti2, Olivier Trédan3, Muriel Le Romancer3, Tie-Liu Shi 1 and Jean-Marc Vanacker2,3* Abstract Background Transcription factors (TFs) act together with co-regulators to modulate the expression of their target genes, which eventually dictates their pathophysiological effects. Depending on the co-regulator, TFs can exert different activities. The Estrogen Related Receptor α (ERRα) acts as a transcription factor that regulates several pathophysiological phenomena. In particular, interactions with PGC-1 co-activators are responsible for the metabolic activities of ERRα . In breast cancers however, ERRα exerts several tumor-promoting, metabolism-unrelated activities that do not depend on PGC-1, questioning the identity of the co-activators involved in these cancer-related effects. Methods Bio-computing methods were used to identify a potential ERRα coactivating factor in aggressive breast cancers. Bench experiments (qPCR, ChIP, proximity ligation assays) were used to validate the effect of the co-factor on ERRα transcriptional activity specifically in triple negative breast cancer (TNBC) cells. Predictive value of ERRα-co-factor target genes on the survival ofTNBC patients was studied. Results ZEB1 appears as a major ERRα co-factor, involved in increased expression of direct ERRα targets that induce cell migration inTNBCs. Experimental validations establish that ERRα and ZEB1 interact together and are bound to the promoters ofthe target genes that they transcriptionally coregulate. Further analyses show that the ERRα-ZEB1 downstream transcriptional signature can predict the survival ofTNBC patients. Conclusions Our approach combining bio-computing as well as experimental validation allows to propose a gene signature, the high expression of which predictsTNBC patient survival. Down modulation of these genes could be promising against TNBCs. Keywords Transcription, Breast cancer, Co-regulators, ERRα, ZEB1 *Correspondence: Jean-Marc Vanacker [jean-marc.vanacker@lyon.unicancer.fr](jean-marc.vanacker@lyon.unicancer.fr) 1The Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, Institute for Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China 2Institut de Génomique Fonctionnelle de Lyon, Université Claude Bernard Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, Lyon 69007, France 3Centre de Recherche en Cancérologie de Lyon, CNRS UMR5286, INSERMU1052, Université Claude Bernard Lyon I, Lyon, France © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-

FAQs

What is the main purpose of the study on ERRα and ZEB1 in TNBC?

To identify whether an ERRα co-activating factor drives tumor-promoting, metabolism-independent effects in triple-negative breast cancer, and to test whether downstream genes predict patient survival.

Which co-factor is reported as central to ERRα activity in the results?

ZEB1 is presented as a major ERRα co-factor that increases expression of direct ERRα targets linked to cell migration in TNBC.

How does the study assess the predictive value for patient outcomes?

It analyzes whether ERRα–ZEB1 downstream transcriptional signature genes predict survival of TNBC patients, supported by proposed gene-expression patterns and down-modulation potential.

Sep 22, 2026

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