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

Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, Toy W, Green B, Panchamukhi S, Katzenellenbogen BS, Tajkhorshid E, Griffin PR, Shen Y, Chandarlapaty S, Katzenellenbogen JA, Greene GL
Elife 5 (2016)
Related entries: 4pxm, 4q13

Cited: 144 times
EuropePMC logo PMID: 26836308

Abstract

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.

Reviews - 4q50 mentioned but not cited (2)

  1. The physiological role of estrogen receptor functional domains. Arao Y, Korach KS. Essays Biochem 65 867-875 (2021)
  2. Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens. Mazurek AH, Szeleszczuk Ł, Simonson T, Pisklak DM. Int J Mol Sci 21 E6411 (2020)

Articles - 4q50 mentioned but not cited (3)

  1. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, Toy W, Green B, Panchamukhi S, Katzenellenbogen BS, Tajkhorshid E, Griffin PR, Shen Y, Chandarlapaty S, Katzenellenbogen JA, Greene GL. Elife 5 e12792 (2016)
  2. The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells. Fanning SW, Jeselsohn R, Dharmarajan V, Mayne CG, Karimi M, Buchwalter G, Houtman R, Toy W, Fowler CE, Han R, Lainé M, Carlson KE, Martin TA, Nowak J, Nwachukwu JC, Hosfield DJ, Chandarlapaty S, Tajkhorshid E, Nettles KW, Griffin PR, Shen Y, Katzenellenbogen JA, Brown M, Greene GL. Elife 7 e37161 (2018)
  3. A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers. Pavlin M, Spinello A, Pennati M, Zaffaroni N, Gobbi S, Bisi A, Colombo G, Magistrato A. Sci Rep 8 649 (2018)


Reviews citing this publication (47)

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Articles citing this publication (92)

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