Abstract

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ER��) 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 ER�� 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 ER�� mutations.

Details

Title
The SERM/SERD Bazedoxifene Disrupts ESR1 Helix 12 to Overcome Acquired Hormone Resistance in Breast Cancer Cells
Author
Fanning, Sean W; Jeselsohn, Rinath; Venkatasubramanian Dharmarajan; Mayne, Christopher G; Karimi, Mostafa; Buchwalter, Gilles; Ren�� Houtman; Toy, Weiyi; Fowler, Colin E; Laine, Muriel; Carlson, Kathryn E; Martin, Teresa A; Nowak, Jason; Nwachukwu, Jerome C; Hosfield, David J; Chandarlapaty, Sarat; Tajkhorshid, Emad; Nettles, Kendall W; Griffin, Patrick R; Shen, Yang; Katzenellenbogen, John A; Brown, Myles; Greene, Geoffrey L
University/institution
Cold Spring Harbor Laboratory Press
Section
New Results
Publication year
2018
Publication date
Apr 23, 2018
Publisher
Cold Spring Harbor Laboratory Press
Source type
Working Paper
Language of publication
English
DOI
https://doi.org/10.1101/306472
ProQuest document ID
2068835292
Copyright
�� 2018. This article is published under http://creativecommons.org/licenses/by/4.0/ (���the License���). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.