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


Authors: Fanning, S. W.; Mayne, C. G.; Dharmarjan, V.; Carlson, K. E.; Martin, T. A.; Novick, S. J.; Toy, W.; Green, B.; Panchamukhi, S.; Katzenellenbogen, B. S.; Tajkhorshid, E.; Griffin, P. R.; Shen, Y.; Chandarlapaty, S.; Katzenellenbogen, J. A.; Greene, G. L.
Article Title: 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 (ER alpha) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ER alpha 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 ER alpha. 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 ER alpha, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.
Keywords: proteins; tamoxifen; software; mechanism; force-field; xenografts; crystal-structure; selectivity; molecular-dynamics; exchange mass-spectrometry
Journal Title: eLife
Volume: 5
ISSN: 2050-084X
Publisher: eLife Sciences Publications Ltd.  
Date Published: 2016-02-02
Start Page: e12792
Language: English
ACCESSION: WOS:000373826700001
DOI: 10.7554/eLife.12792
PROVIDER: wos
PMCID: PMC4821807
PUBMED: 26836308
Notes: Article -- Source: Wos
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  1. Weiyi Toy
    19 Toy