Estrogen receptor signaling without estrogen: molecular insights into hormone resistance

Estrogen receptor alpha (ERα) is thought to be a ligand-dependent transcription factor. Increasing number of data suggest that ERα is able to retain its transcriptional activity without stimulation by estrogen and therefore contributes to development of endocrine resistance in hormone receptor-positive cancers. The objective of this paper is to overview molecular mechanisms of ligand-independent activation of ERα and to address the clinical significance of these mechanisms.

A detailed literature review of recent experimental, translational and clinical studies has been performed with the aim of exploring molecular mechanisms of ligand-independent ERα activation, clinical significance of these mechanisms, and their application to molecular diagnostics and targeted therapy.

There are several ways of maintaining transcriptional activity of ERα in the absence of estrogen ligand. They include ESR1 mutations and gene fusions, alterations in signaling pathways involving growth factor receptors, abnormalities in regulation by co-regulators, epigenetic rewiring, and post-translational modifications. These changes contribute to endocrine resistance and might explain the discordance between expression of ER determined by immunohistochemical staining and clinical response to endocrine therapy.

The recognition of signaling by ERα that is not ligand-dependent will lead to an expansion of knowledge about the estrogen receptor and the shortcomings of depending only on immunohistochemical ER status for decision making in treatment. It might be beneficial for the prediction of patients' sensitivity to endocrine treatment by adding molecular biomarkers related to the activity of the ERα.