Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 02, 2016
- Source ID
- 10.7554/elife.12792
Entities
People
- Benita Katzenellenbogen
- Bradley Green
- Christopher G Mayne
- Emad Tajkhorshid
- Geoffrey L Greene
- John Katzenellenbogen
- Kathryn E. Carlson
- Patrick R Griffin
- Sarat Chandarlapaty
- Scott J Novick
- Sean W Fanning
- Srinivas Panchamukhi
- Teresa A Martin
- Venkatasubramanian Dharmarajan
- Weiyi Toy
- Yang Shen
Organizations
- Ludwig Institute for Cancer Research
- Memorial Sloan Kettering Cancer Center
- National Institutes of Health
- National Science Foundation
- Scripps Research
- Susan G. Komen for the Cure
- Texas A&M University
- United States Department of Defense
- University of Chicago
- University of Illinois Urbana–Champaign