PT  - JOURNAL ARTICLE
AU  - Sean W. Fanning
AU  - Rinath Jeselsohn
AU  - Venkatasubramanian Dharmarajan
AU  - Christopher G. Mayne
AU  - Mostafa Karimi
AU  - Gilles Buchwalter
AU  - Rene Houtman
AU  - Weiyi Toy
AU  - Colin E. Fowler
AU  - Muriel Lainé
AU  - Kathryn E Carlson
AU  - Teresa A. Martin
AU  - Jason Nowak
AU  - Jerome Nwachukwu
AU  - David J. Hosfield
AU  - Sarat Chandarlapaty
AU  - Emad Tajkhorshid
AU  - Kendall W. Nettles
AU  - Patrick R. Griffin
AU  - Yang Shen
AU  - John A. Katzenellenbogen
AU  - Myles Brown
AU  - Geoffrey L. Greene
TI  - The SERM/SERD Bazedoxifene Disrupts ESR1 Helix 12 to Overcome Acquired Hormone Resistance in Breast Cancer Cells
AID  - 10.1101/306472
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 306472
4099  - http://biorxiv.org/content/early/2018/04/23/306472.short
4100  - http://biorxiv.org/content/early/2018/04/23/306472.full
AB  - Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα) 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 find BZA possesses improved inhibitory potency against the Y537S and D538G ERα 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 that BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.Significance Bazedoxifene (BZA) is a potent orally available antiestrogen that is clinically approved for use in hormone replacement therapy (DUAVEE). We explore the efficacy of BZA to inhibit activating somatic mutants of ERα that can arise in metastatic breast cancers after prolonged exposure to aromatase inhibitors or tamoxifen therapy. Breast cancer cell line, biophysical, and structural data show that BZA disrupts helix 12 of the ERα ligand binding domain to achieve improved potency against Y537S and D538G somatic mutants compared to 4-hydroxytamoxifen.