miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer
Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast...
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2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8086 |
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| author | Mithil Soni Ozge Saatci Gourab Gupta Yogin Patel Manikanda Raja Keerthi Raja Jie Li Xinfeng Liu Peisheng Xu Hongjun Wang Daping Fan Ozgur Sahin Hexin Chen |
| author_facet | Mithil Soni Ozge Saatci Gourab Gupta Yogin Patel Manikanda Raja Keerthi Raja Jie Li Xinfeng Liu Peisheng Xu Hongjun Wang Daping Fan Ozgur Sahin Hexin Chen |
| author_sort | Mithil Soni |
| collection | DOAJ |
| description | Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:36:32Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-07cc7b5019044ebf988b6ddb7d0fdbc12023-11-30T22:23:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012315808610.3390/ijms23158086miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast CancerMithil Soni0Ozge Saatci1Gourab Gupta2Yogin Patel3Manikanda Raja Keerthi Raja4Jie Li5Xinfeng Liu6Peisheng Xu7Hongjun Wang8Daping Fan9Ozgur Sahin10Hexin Chen11Department of Biological Science, University of South Carolina, Columbia, SC 29208, USADepartment of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USADepartment of Biological Science, University of South Carolina, Columbia, SC 29208, USADepartment of Biological Science, University of South Carolina, Columbia, SC 29208, USADepartment of Biological Science, University of South Carolina, Columbia, SC 29208, USADepartment of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29201, USADepartment of Mathematics, University of South Carolina, Columbia, SC 29201, USADepartment of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USADepartment of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USADepartment of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USADepartment of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USADepartment of Biological Science, University of South Carolina, Columbia, SC 29208, USAApproximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.https://www.mdpi.com/1422-0067/23/15/8086miR-489breast cancerestrogen receptortamoxifen resistanceCRISPR/Cas9 |
| spellingShingle | Mithil Soni Ozge Saatci Gourab Gupta Yogin Patel Manikanda Raja Keerthi Raja Jie Li Xinfeng Liu Peisheng Xu Hongjun Wang Daping Fan Ozgur Sahin Hexin Chen miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer International Journal of Molecular Sciences miR-489 breast cancer estrogen receptor tamoxifen resistance CRISPR/Cas9 |
| title | miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer |
| title_full | miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer |
| title_fullStr | miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer |
| title_full_unstemmed | miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer |
| title_short | miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer |
| title_sort | mir 489 confines uncontrolled estrogen signaling through a negative feedback mechanism and regulates tamoxifen resistance in breast cancer |
| topic | miR-489 breast cancer estrogen receptor tamoxifen resistance CRISPR/Cas9 |
| url | https://www.mdpi.com/1422-0067/23/15/8086 |
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