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Published on: July 25, 2020
Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their
Frederik Holst1,2,3,4, Erling A Hoivik1,2, William J Gibson3,4,5,6
1Centre for Cancer Biomarkers, Department of Clinical Science, The University of Bergen, Norway.
Abstract:
The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be effective in endometrial cancer. Recently it has been shown that hormone-binding domain alterations of ERα in breast cancer contribute to acquired resistance to anti-estrogen therapy. In analyses of genomic data from The Cancer Genome Atlas (TCGA), we observe that endometrial carcinomas manifest recurrent ESR1 gene amplifications that truncate the hormone-binding domain encoding region of ESR1 and are associated with reduced mRNA expression of exons encoding the hormone-binding domain. These findings support a role for hormone-binding alterations of ERα in primary endometrial cancer, with potentially important therapeutic implications.
Insights
Endometrial cancer, unlike breast cancer, is resistant to anti-estrogen therapy. Genomic analysis revealed ESR1 gene amplifications in endometrial tumors, suggesting hormone-binding domain alterations may drive this resistance.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Estrogen receptor alpha (ERα) is a key target in breast cancer therapy but not endometrial cancer.
- Alterations in ERα's hormone-binding domain are linked to resistance to anti-estrogen treatments in breast cancer.
- Endometrial cancer exhibits distinct responses to endocrine therapies compared to breast cancer.
Purpose of the Study:
- To investigate the role of ERα alterations in endometrial cancer.
- To explore potential mechanisms behind anti-estrogen therapy resistance in endometrial cancer.
- To analyze genomic data for recurrent mutations or amplifications in the ESR1 gene in endometrial carcinomas.
Main Methods:
- Analysis of genomic data from The Cancer Genome Atlas (TCGA).
- Examination of ESR1 gene amplifications and their impact on the hormone-binding domain.
- Assessment of mRNA expression levels related to the hormone-binding domain.
Main Results:
- Endometrial carcinomas show recurrent amplifications of the ESR1 gene.
- These amplifications lead to truncation of the hormone-binding domain encoding region of ESR1.
- Associated with these amplifications is reduced mRNA expression of exons encoding the hormone-binding domain.
Conclusions:
- Hormone-binding domain alterations of ERα play a role in primary endometrial cancer.
- These findings suggest potential therapeutic strategies targeting ERα in endometrial cancer.
- Understanding ERα alterations may improve treatment outcomes for endometrial cancer patients.
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