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  • Review Article
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The different roles of ER subtypes in cancer biology and therapy

Nature Reviews Cancer volume 11, pages 597–608 (2011)Cite this article

Subjects

Key Points

  • Oestrogen receptor (ER) subtypes (ERα and ERβ) influence the development and progression of hormone-related cancers by exerting distinct biological functions. ERα is associated with aberrant proliferation, inflammation and the development of malignancy. ERβ seems to oppose ERα actions on cell proliferation by modulating the expression of many ERα-regulated genes and exhibits antimigratory and anti-invasive properties in cancer cells.

  • Multiple factors affect the ER-mediated regulation of gene expression and may account for the adverse and beneficial effects of oestrogens and anti-oestrogens. Both ER genomic and non-genomic actions often converge at certain regulatory sites of the adjacent ER-responsive genes. The final gene and the subsequent cancer biological responses may vary depending on the combination of transcription factors; the ratio and the cellular localization of ERα and ERβ; the expression levels of various co-regulators and signal transduction components; and the nature of extracellular stimuli. These variables are altered during cancer transformation and are divergent in different cancer cells.

  • Owing to the practical limitations in detection, only a few truncated ERα and ERβ variant isoforms have been examined in tumour samples and correlated with clinical outcome. Some of these variants are localized in the cytoplasm and plasma membrane, show variable expression in cancer tissues and influence cancer progression and response to therapy either through genomic pathways by modulating the activity of wild-type ERs or by interacting with the membrane and cytoplasmic signalling cascade.

  • Perturbation of ER subtype-specific expression has been detected in different stages of various types of cancer, with the levels of ERα and ERβ declining in most cancers as the disease develops. The hypermethylation of the ER promoters, microRNAs that target the ER mRNAs and increased proteasomal degradation are among the factors that are responsible for the reduced levels of ERs in cancer tissues.

  • ERα is the principal biomarker for the response of breast cancers to endocrine therapy, and its truncated isoform ERα-36 seems to confer resistance to tamoxifen. On-going research is trying to fully clarify the prognostic and predictive role of ERβ. So far, it seems that the nuclear wild-type ERβ complements ERα in predicting response to endocrine therapy and is associated with better overall outcome and the metastatic potential of breast and prostate cancer. The cytoplasmic ERβ2 (also known as ERβcx) isoform correlates with worse survival and metastatic phenotype.

  • Insights into the mechanisms of ER action and regulation have suggested possible therapeutic approaches for hormone-related cancers. The development of selective ERα and ERβ agonists and antagonists, and alternative strategies that target the ER signalling beyond the ligand-binding activity, including as targets components of growth factor signalling, methylases, ubiquitin ligases, and chaperones are under investigation.

Abstract

By eliciting distinct transcriptional responses, the oestrogen receptors (ERs) ERα and ERβ exert opposite effects on cellular processes that include proliferation, apoptosis and migration and that differentially influence the development and the progression of cancer. Perturbation of ER subtype-specific expression has been detected in various types of cancer, and the differences in the expression of ERs are correlated with the clinical outcome. The changes in the bioavailability of ERs in tumours, together with their specific biological functions, promote the selective restoration of their activity as one of the major therapeutic approaches for hormone-dependent cancers.

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Figure 1: Schematic representation of structural and functional domains of the ERs.
Figure 2: Molecular mechanism of ER action.
Figure 3: Regulation of the cellular levels of ERs.

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Acknowledgements

Research in the authors' laboratory is supported by the Welch Foundation and the Texas Emergency Technology Fund, under Agreement No 300-9-1958.

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Authors and Affiliations

  1. Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signalling, University of Houston, Texas, 77204, Houston, USA

    Christoforos Thomas & Jan-Åke Gustafsson

  2. Department of Biosciences and Nutrition, Novum, Karolinska Institute, S-14183, Huddinge, Sweden

    Jan-Åke Gustafsson

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Correspondence to Jan-Åke Gustafsson.

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Glossary

Co-activators

Proteins that increase gene expression by binding to a transcription factor that binds DNA through its DNA-binding domain.

Co-repressors

Proteins that decrease gene expression by binding to a transcription factor that contains a DNA-binding domain.

'Pure' anti-oestrogens

Drugs that bind the oestrogen receptor, thereby blocking the effect of oestrogen, but that have no detectable oestrogen-like effects. Most have a steroidal structure.

Gleason grade

The assignment of a number between 1 and 5 to indicate the degree of differentiation of the cells in the cancer specimen. It is used to establish the Gleason score. Cancers with a higher Gleason score are more aggressive and have a worse prognosis.

Hormone replacement therapy

(HRT). The administration of hormones to correct a deficiency, such as postmenopausal oestrogen replacement therapy.

SERMs

Drugs that bind the oestrogen receptor and thereby block the effects of oestrogen on tissues such as the breast but that function similarly to oestrogen in other tissues, such as the endometrium. These drugs are not steroidal in structure.

Aromatase inhibitors

Drugs that block aromatase, the enzyme that converts androgens to oestrogens in tissues including the breast and adipose tissue.

Unfolded protein response

A cellular response to stress that senses misfolded proteins in the endoplasmic reticulum. It activates pathways that help cells to survive the toxicity that is caused by unfolded proteins or to activate mechanisms of cell death.

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Thomas, C., Gustafsson, JÅ. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 11, 597–608 (2011). https://doi.org/10.1038/nrc3093

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