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Elife. 2016 Feb 2;5. pii: e12792. doi: 10.7554/eLife.12792.

Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.

Author information

1
Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
2
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, United States.
3
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.
4
Department of Biochemistry, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States.
5
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
7
Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, United States.
8
Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, 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.

KEYWORDS:

acquired drug resistance; biophysics; breast cancer; estrogen receptor alpha; hormone; human; human biology; medicine; selective estrogen receptor modulators; somatic mutation; structural biology

PMID:
26836308
PMCID:
PMC4821807
DOI:
10.7554/eLife.12792
[Indexed for MEDLINE]
Free PMC Article
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