Related Experiment Video

Updated: Jan 26, 2026

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

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Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed

Stéphanie L Gaillard1, Kaitlyn J Andreano2, Laurie M Gay3

  • 1Duke University Medical Center, Durham, NC, United States of America; Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD, United States of America.

Gynecologic Oncology
|April 17, 2019
PubMed
Abstract

Insights

Genomic alterations in the estrogen receptor (ESR1) gene are found in 3.0% of gynecologic cancers. While rare, these ESR1 mutations can impact endocrine therapy response and guide treatment decisions.

Area of Science:

  • Gynecologic Oncology
  • Genomic Medicine
  • Endocrinology

Background:

  • Endocrine therapy is a cornerstone for hormone-responsive gynecologic malignancies.
  • Activating mutations in the estrogen receptor (mutESR1) are known to cause resistance to endocrine therapy in breast cancer.
  • The clinical relevance of ESR1 genomic alterations in gynecologic cancers remains to be fully elucidated.

Purpose of the Study:

  • To determine the frequency of ESR1 genomic alterations in a large cohort of gynecologic malignancies.
  • To investigate the clinical significance of these alterations in relation to endocrine therapy outcomes.
  • To characterize the behavior of mutESR1 under selective pressure of therapy.

Main Methods:

  • Next-generation sequencing of DNA from 9645 FFPE gynecologic tumor tissues.
  • Analysis encompassed all classes of genomic alterations in the ESR1 gene.
  • Functional characterization of a subset of alterations using laboratory-based transcription assays.

Main Results:

  • 295 ESR1 genomic alterations were identified in 285 (3.0%) cases.
  • mutESR1 were found in 0.9% of cases, with higher prevalence in uterine cancers and endometrioid histology.
  • mutESR1 emerged under aromatase inhibitor pressure in serial samples, and patients showed clinical benefit from ER-targeted therapy.

Conclusions:

  • ESR1 mutations are infrequent in gynecologic malignancies but hold significant clinical implications.
  • Understanding ESR1 alteration frequency and behavior can guide therapeutic strategies.
  • These findings highlight the potential for targeted therapies in specific gynecologic cancer subsets.

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