ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation
Abstract The constitutively active ESR1 Y537S mutation is associated with endocrine therapy (ET) resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ERα) gene regulatory functions. However, the complex relationship between ERα and the progesterone recepto...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-023-00601-7 |
| _version_ | 1797414364582510592 |
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| author | Rosemary J. Huggins Geoffrey L. Greene |
| author_facet | Rosemary J. Huggins Geoffrey L. Greene |
| author_sort | Rosemary J. Huggins |
| collection | DOAJ |
| description | Abstract The constitutively active ESR1 Y537S mutation is associated with endocrine therapy (ET) resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ERα) gene regulatory functions. However, the complex relationship between ERα and the progesterone receptor (PR), known as ERα/PR crosstalk, has yet to be characterized in the context of the ERα Y537S mutation. Using proximity ligation assays, we identify an increased physical interaction of ERα and PR in the context of the ERα Y537S mutation, including in the nucleus where this interaction may translate to altered gene expression. As such, more than 30 genes were differentially expressed in both patient tumor and cell line data (MCF7 and/or T47D cells) in the context of the ERα Y537S mutation compared to ERα WT. Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 had a significant anti-proliferative effect in ERα Y537S cell lines, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations. |
| first_indexed | 2024-03-09T05:32:00Z |
| format | Article |
| id | doaj.art-24ae94823dee4b25a45912cce95203f1 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-09T05:32:00Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-24ae94823dee4b25a45912cce95203f12023-12-03T12:31:26ZengNature Portfolionpj Breast Cancer2374-46772023-11-019111310.1038/s41523-023-00601-7ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferationRosemary J. Huggins0Geoffrey L. Greene1Ben May Department for Cancer Research, University of ChicagoBen May Department for Cancer Research, University of ChicagoAbstract The constitutively active ESR1 Y537S mutation is associated with endocrine therapy (ET) resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ERα) gene regulatory functions. However, the complex relationship between ERα and the progesterone receptor (PR), known as ERα/PR crosstalk, has yet to be characterized in the context of the ERα Y537S mutation. Using proximity ligation assays, we identify an increased physical interaction of ERα and PR in the context of the ERα Y537S mutation, including in the nucleus where this interaction may translate to altered gene expression. As such, more than 30 genes were differentially expressed in both patient tumor and cell line data (MCF7 and/or T47D cells) in the context of the ERα Y537S mutation compared to ERα WT. Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 had a significant anti-proliferative effect in ERα Y537S cell lines, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations.https://doi.org/10.1038/s41523-023-00601-7 |
| spellingShingle | Rosemary J. Huggins Geoffrey L. Greene ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation npj Breast Cancer |
| title | ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation |
| title_full | ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation |
| title_fullStr | ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation |
| title_full_unstemmed | ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation |
| title_short | ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation |
| title_sort | erα pr crosstalk is altered in the context of the erα y537s mutation and contributes to endocrine therapy resistant tumor proliferation |
| url | https://doi.org/10.1038/s41523-023-00601-7 |
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