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

https://synapse.mskcc.org/synapse/works/has_related_data_chk/94023