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

• Main Authors: Sean W Fanning, Christopher G Mayne, Venkatasubramanian Dharmarajan, Kathryn E Carlson, Teresa A Martin, Scott J Novick, Weiyi Toy, Bradley Green, Srinivas Panchamukhi, Benita S Katzenellenbogen, Emad Tajkhorshid, Patrick R Griffin, Yang Shen, Sarat Chandarlapaty, John A Katzenellenbogen, Geoffrey L Greene
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2016-02-01
• Series: eLife
• Subjects: breast cancer; acquired drug resistance; somatic mutation; estrogen receptor alpha; hormone; selective estrogen receptor modulators
• Online Access: https://elifesciences.org/articles/12792

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.