Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

• Published in: Nature reviews. Cancer Vol. 18; no. 6; pp. 377 - 388
• Main Authors: Katzenellenbogen, John A, Mayne, Christopher G, Katzenellenbogen, Benita S, Greene, Geoffrey L, Chandarlapaty, Sarat
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2018
• Subjects: Activation; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Antineoplastic Agents, Hormonal - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Development and progression; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Endocrine therapy; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogens - metabolism; Female; Genetic aspects; Health aspects; Hormone therapy; Humans; Ligands; Male; Metastases; Mutants; Mutation; Phenotypes; Prostate; Prostate cancer; Prostatic Neoplasms - drug therapy; Protein Binding; Protein Conformation; Protein Domains; Protein structure; Receptors, Androgen - genetics; Single nucleotide polymorphisms; United States
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/s41568-018-0001-z

Oestrogen receptor-α (ERα), a key driver of breast cancer, normally requires oestrogen for activation. Mutations that constitutively activate ERα without the need for hormone binding are frequently found in endocrine-therapy-resistant breast cancer metastases and are associated with poor patient outcomes. The location of these mutations in the ER ligand-binding domain and their impact on receptor conformation suggest that they subvert distinct mechanisms that normally maintain the low basal state of wild-type ERα in the absence of hormone. Such mutations provide opportunities to probe fundamental issues underlying ligand-mediated control of ERα activity. Instructive contrasts between these ERα mutations and those that arise in the androgen receptor (AR) during anti-androgen treatment of prostate cancer highlight differences in how activation functions in ERs and AR control receptor activity, how hormonal pressures (deprivation versus antagonism) drive the selection of phenotypically different mutants, how altered protein conformations can reduce antagonist potency and how altered ligand-receptor contacts can invert the response that a receptor has to an agonist ligand versus an antagonist ligand. A deeper understanding of how ligand regulation of receptor conformation is linked to receptor function offers a conceptual framework for developing new anti-oestrogens that might be more effective in preventing and treating breast cancer.