The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells

Sean W. Fanning, Rinath Jeselsohn, Venkatasubramanian Dharmarajan, Christopher G. Mayne, Mostafa Karimi, Gilles Buchwalter, René Houtman, Weiyi Toy, Colin E. Fowler, Ross Han, Muriel Lainé, Kathryn E. Carlson, Teresa A. Martin, Jason Nowak, Jerome C. Nwachukwu, David J. Hosfield, Sarat Chandarlapaty, Emad Tajkhorshid, Kendall W. Nettles, Patrick R. GriffinYang Shen, John A. Katzenellenbogen, Myles Brown, Geoffrey L. Greene

Research output: Contribution to journalArticlepeer-review

Abstract

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERa)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERa mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.

Original languageEnglish (US)
Article numbere37161
JournaleLife
Volume7
DOIs
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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