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Ludwig Fund for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006352","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Somatic mutations in the estrogen receptor alpha (ER\u03b1) gene (\n                    <jats:italic>ESR1<\/jats:italic>\n                    ), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ER\u03b1 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\u03b1. 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\u03b1, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.\n                  <\/jats:p>","DOI":"10.7554\/elife.12792","type":"journal-article","created":{"date-parts":[[2016,2,2]],"date-time":"2016-02-02T07:37:41Z","timestamp":1454398661000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.12792","source":"Crossref","is-referenced-by-count":286,"title":["Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation"],"prefix":"10.7554","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9428-0060","authenticated-orcid":true,"given":"Sean W","family":"Fanning","sequence":"first","affiliation":[{"name":"Ben May Department for Cancer Research, University of Chicago, 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