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.
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The authors thank their numerous co-workers for their research efforts. Grant support of much of the work described in this Opinion piece from the following sources: the US National Institutes of Health (PHS R01DK015556 to J.A.K., P41GM104601 and T32GM070421 to the University of Illinois, 5R01CA20499 to S.C., P30CA008748 to Memorial Sloan Kettering Cancer Center and P30CA14599 to the University of Chicago Cancer Center), the Virginia and D.K. Ludwig Fund for Cancer Research (to G.L.G.), the US Department of Defense (DOD BC131458 to G.L.G.) and the Breast Cancer Research Foundation (BCRF 17–083 to J.A.K. and B.S.K. and BCRF 17-082 to B.S.K.).
The authors declare no competing financial interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Nature Reviews Cancer thanks J. Carroll, V. C. Jordan and R. Schiff for their contribution to the peer review of this work.
cBioPortal database: http://www.cbioportal.org/study?id=msk_impact_2017#summary
Electronic supplementary material
Supplementary Movie 1: Activating Mutations in ER – Outside of the ER Ligand Binding Pocket. ERα LBD dimer showing the locations of the activating mutations (green) relative to the ligand (estradiol), the coactivator helix (orange cylinder) and the AF2 coactivator binding region (yellow helices). Monomers are colored blue and gray, and the h9-h10 loop is red. All of the mutations are far from the ligand binding pocket.
Supplementary Movie 2: Activating Mutations in AR – Inside the AR Ligand Binding Pocket. AR LBD monomer showing the locations of the activating mutations (green) relative to the ligand (testosterone), and the AF2 coactivator binding region (yellow helices). All of the AR mutations are inside the ligand binding pocket in contact with the ligand. The extension of h12 can be seen as a kink in the helix, followed by a strand that makes a β-sheet with the h9-h10 loop region and interferes with the dimerization site used by ERα LBD dimers.
Supplementary Movie 3: ER and AR LBDs Overlapped Showing the Locations of the Mutations Relative to the Ligand Binding Pocket. Overlay of ERα LBD (light blue) and the AR LBD (light red) showing the different locations of endocrine therapy resistance mutations (ER – dark blue outside of the LBP, estradiol; AR – dark red, within the LBP). The structure extends beyond the end of h12 in the structure of the AR LBD but not in the ER LBD structure.
- Activation functions
Regions of amino acid sequence or 3D structure in transcription factors that are associated with the activation of transcription.
- Androgen receptor
(AR). A transcription factor that is a member of the nuclear hormone receptor superfamily. It is the principal mediator of the biological effects of androgens and a major driver of the proliferation and progression of prostate cancer.
A ligand for the oestrogen receptor (ER) used as one form of endocrine therapy for breast cancer. Anti-oestrogens bind to ER and alter its conformation so that it is unable to stimulate the proliferation and progression of breast cancer cells.
A term that indicates that a binding protein is in its unliganded state.
- Aromatase inhibitors
Used as a form of endocrine therapy for breast cancer that works by blocking the production of oestrogens by the ovaries and other tissues, such as the adrenals, and by the tumour itself.
- Conservative mutation
The replacement of a residue in a protein with one that has similar physical properties.
- Coulombic repulsion
A force separating two entities of equal charge, either positive–positive or negative–negative, when they are close in space.
- Heat shock proteins
(HSPs). A family of proteins that selectively bind other proteins that are intrinsically or aberrantly unfolded. HSP90 is the major protein to which wild-type apo-ERα binds, although other HSPs also likely participate in this binding.
- Ligand-binding domain
(LBD). A domain of the oestrogen receptor (ER) responsible for binding oestrogens and anti-oestrogens. It is domain E out of the domains A–F and stretches approximately from amino acid 304 to 554 out of a total of 595 amino acids, accounting for about 40% of the overall length of ERα. It is composed of 12 α-helices and a few β-strand elements that make up the secondary structure.
- Ligand-binding pocket
(LBP). An interior region of the ligand-binding domain within which both agonist and antagonist ligands bind, with occasional portions of the ligands extending beyond the confines of the pocket.
- Molecular dynamics modelling
(MDM). A computationally intensive method for exploring the conformation and dynamic features of proteins by providing alternating inputs of velocity on individual atoms and relaxation within the energy force field confines of the protein.
- Nuclear receptors
A superfamily of proteins of which the oestrogen receptor-α (ERα) and the androgen receptor (AR) are members. Most members of the superfamily function largely as transcription factors, many of which are regulated by the binding of ligands, which can be endogenous metabolites (hormones) or exogenous ligands (pharmaceuticals, xenobiotics and so on).
- Oestrogen receptor-α
(ERα). A transcription factor that is a member of the nuclear hormone receptor superfamily. The ERα subtype is the principal mediator of the biological effects of oestrogens and a major driver of the proliferation and progression of breast cancer. ERα is distinguished from another ER subtype, ERβ, which has very different biological activities that are largely unrelated to driving breast cancer progression.
A steroid with an aromatic A ring that is the principal endogenous oestrogen hormone that drives the proliferation and progression of breast cancer cells.
- Selective oestrogen receptor modulator
(SERM). A class of oestrogen receptor-α (ERα) ligands that can have tissue-selective pharmacological effects, acting as agonists in some tissues (such as bone and vascular tissues) and antagonists in others (such as breast and uterine tissues). SERMs such as tamoxifen are used in breast cancer endocrine therapy; other SERMs such as raloxifene are used in hormone replacement therapies to protect bone in postmenopausal women.
- Selective oestrogen receptor downregulator
(SERD). A class of oestrogen receptor-α (ERα) ligands such as fulvestrant that cause a reduction in the levels of the ERα protein; they also function as ER antagonists and are used in breast cancer endocrine therapies.
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Katzenellenbogen, J.A., Mayne, C.G., Katzenellenbogen, B.S. et al. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Nat Rev Cancer 18, 377–388 (2018). https://doi.org/10.1038/s41568-018-0001-z
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