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, ERRα exerts several tumor-promoting, metabolism-unrelated activities that do not depend on PGC1, questioning the identity of the co-activators involved in these cancer-related effects.

Methods.

We used bio-computing methods to identify potential co-factors that could be responsible for the activities of ERRα in cancer progression. Experimental validations were conducted in different breast cancer cell lines, using determination of mRNA expression, ChIP-qPCR and proximity ligation assays.

Results.

ZEB1 is proposed as a major ERRα co-factor that could be responsible for the expression of direct ERRα targets in triple-negative breast cancers (TNBC). We establish that ERRα and ZEB1 interact together and are bound to the promoters of their target genes that they transcriptionally regulate. Our further analyses show that the ERRα-ZEB1 downstream signature can predict the survival of the TNBC patients.

Conclusions.

The ERRα-ZEB1 complex is a major actor in breast cancer progression and expression of its downstream transcriptional targets can predict the overall survival of triple-negative breast cancer patients.