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The ESR1 Mutations: From Bedside to Bench to Bedside
Francisco Hermida-Prado1,2, Rinath Jeselsohn3,2,4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Cancer Research
|February 2, 2021
Summary
New models reveal how estrogen receptor 1 (ESR1) mutations drive resistance to endocrine therapies like aromatase inhibitors. These activating ESR1 mutations lead to continuous receptor activity, even without estrogen, explaining treatment failure.
Area of Science:
- Endocrinology
- Genetics
- Cancer Biology
Background:
- Estrogen receptor 1 (ESR1) ligand-binding domain mutations are the primary cause of acquired resistance to endocrine treatments, especially aromatase inhibitors.
- These mutations confer constitutive, ligand-independent activity to the estrogen receptor, explaining their emergence under selective pressure.
Purpose of the Study:
- To generate and characterize novel models of ESR1 ligand-binding domain mutations.
- To elucidate the functional consequences of these activating ESR1 mutations.
Main Methods:
- Utilized CRISPR technology to generate single-cell-derived clones with knocked-in ESR1 ligand-binding mutations.
- Expressed mutated ESR1 under its endogenous promoter in the generated models.
Main Results:
- Successfully created and extensively characterized novel models of ESR1 mutations.
- These models provide new insights into the functional impact of ESR1 mutations.
Conclusions:
- The developed models are crucial for understanding the mechanisms of endocrine resistance driven by ESR1 mutations.
- Further research using these models will illuminate the functional consequences of ESR1 mutations in endocrine therapy resistance.
