TY - JOUR
T1 - Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
AU - Fanning, Sean W.
AU - Mayne, Christopher G.
AU - Dharmarajan, Venkatasubramanian
AU - Carlson, Kathryn E.
AU - Martin, Teresa A.
AU - Novick, Scott J.
AU - Toy, Weiyi
AU - Green, Bradley
AU - Panchamukhi, Srinivas
AU - Katzenellenbogen, Benita S.
AU - Tajkhorshid, Emad
AU - Griffin, Patrick R.
AU - Shen, Yang
AU - Chandarlapaty, Sarat
AU - Katzenellenbogen, John A.
AU - Greene, Geoffrey L.
N1 - Publisher Copyright:
© Fanning et al.
PY - 2016/2/2
Y1 - 2016/2/2
N2 - 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.
AB - 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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U2 - 10.7554/eLife.12792
DO - 10.7554/eLife.12792
M3 - Article
C2 - 26836308
AN - SCOPUS:84978720091
SN - 2050-084X
VL - 5
JO - eLife
JF - eLife
IS - FEBRUARY2016
M1 - e12792
ER -