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
ISSN
2692-8205
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.