Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
- University of Chicago, United States
- University of Illinois at Urbana-Champaign, United States
- The Scripps Research Institute-Scripps Florida, United States
- The Scripps Research Institute, United States
- Memorial Sloan Kettering Cancer Center, United States
- University of Illinois Urbana-Champaign, United States
- Texas A&M University, United States
- Memorial Sloan-Kettering Cancer Center, United States
Abstract
Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.
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© 2016, Fanning et al.
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Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
eLife 5:e12792.
https://doi.org/10.7554/eLife.12792
