The different roles of ER subtypes in cancer biology and therapy

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.