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Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond

Key Points

  • Oestrogen-related receptors (ERRα, ERRβ and ERRγ) were the first orphan members of the nuclear receptor superfamily to be discovered. Because of their structural relationship with the oestrogen receptors (ERs), early studies of possible roles for the ERRs in cancer biology focused on potential functional crosstalk between the two receptors in controlling gene expression in breast cancer cells. However, this fairly simple concept has recently been revisited to reveal functions and genetic programmes that are unique to the ERRs in both normal and cancer cells.

  • The ERRs are expressed in tissues with high energy demands and many cancerous tissues. They have dominant roles in maintaining cellular energy homeostasis through the regulation of vast networks of metabolic genes. The ERRs participate in the control of the expression of genes that encode enzymes of the glycolytic pathway, the tricarboxylic acid cycle, the oxidative phosphorylation apparatus, as well as genes involved in lipid, glutamine, amino acid, nucleic acid and pyruvate metabolism and the energy-sensing machinery.

  • Genomic studies showed that the functional overlap between the ERRs and the ERs as transcription factors is limited in breast cancer cells. The expression of ERRα is inversely correlated with that of ERα and positively correlates with that of the oncogene ERBB2. ERRα is considered a marker of unfavourable prognosis. By contrast, the expression of ERRγ is considered a marker of a better prognosis.

  • In breast cancer cells, mounting evidence suggests that ERRα and ERRγ are required to maintain glycolytic and oxidative metabolic programmes, respectively. The distinct biological functions of these two ERR isoforms are further supported by the observation that a microRNA (miR-378*), regulated by the ERBB2–MYC oncogenic axis, promotes a Warburg-like phenotype via inhibition of ERRγ expression in breast cancer cells. By also sustaining mitochondrial functions involved in anabolic processes required for cell growth and proliferation, the role of the ERRs in reprogramming breast cancer cell metabolism extends beyond promoting the Warburg effect.

  • The ERR pathway integrates with oncogenic signalling such as ERBB2 and MYC to mediate metabolic reprogramming of breast cancer cells. ERRα transcriptional activity is influenced by mitogenic signals such as those controlled by ERBB2 and epidermal growth factor receptor (EGFR). Reciprocally, ERRα regulates the expression of ERBB2.

  • Although the presence of ERRα itself does not predict outcome, the expression of ERRα target genes in breast tumours generates genomic predictors that are associated with outcome of the disease.

  • As the ERRs control universal cellular processes that affect growth and proliferation, it is likely that patients with breast cancer could benefit from therapeutic interventions directed towards the ERRs regardless of their tumour subtype.

Abstract

Oestrogen-related receptors (ERRs) are orphan nuclear receptors that were initially investigated in breast cancer because of their structural relationship to oestrogen receptors. Recent data have shown that the ERRs control vast gene networks that are involved in glycolysis, glutaminolysis, oxidative phosphorylation, nutrient sensing and biosynthesis pathways. In the context of breast cancer, the ERRs affect cellular metabolism in a manner that promotes a Warburg-like phenotype. The ERRs also modulate breast cancer cell metabolism, growth and proliferation through the regulation of key oncoproteins. We discuss the value but also the implications of the complexity of targeting the ERRs for the development of cancer therapeutics.

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Figure 1: Regulation of ERR transcriptional activity.
Figure 2: The potential contrasting influence of ERRα and ERRγ on the metabolic status of breast cancer cells.
Figure 3: Integration of the ERR transcriptional pathway with oncogenic signals in the regulation of cellular energy metabolism in breast cancer cells.
Figure 4: Differential expression of ERRα target genes is associated with known breast cancer subtypes.

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Acknowledgements

The authors gratefully acknowledge J. St-Pierre for critical review and suggestions for the manuscript. The authors' research is supported by the Canadian Institutes for Health Research (MOP-64275) and a Program Project Grant from the Terry Fox Foundation (TFF-116128). G.D. is supported by a predoctoral traineeship award (W81XWH-10-1-0489) from the US Department of Defense Breast Cancer Research Program.

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Correspondence to Vincent Giguère.

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Deblois, G., Giguère, V. Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond. Nat Rev Cancer 13, 27–36 (2013). https://doi.org/10.1038/nrc3396

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