MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit
Abstract Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which mi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-01-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-020-00210-8 |
| _version_ | 1797643153969250304 |
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| author | Sanne Løkkegaard Daniel Elias Carla L. Alves Martin V. Bennetzen Anne-Vibeke Lænkholm Martin Bak Morten F. Gjerstorff Lene E. Johansen Henriette Vever Christina Bjerre Tove Kirkegaard Bo Nordenskjöld Tommy Fornander Olle Stål Linda S. Lindström Laura J. Esserman Anne E. Lykkesfeldt Jens S. Andersen Rikke Leth-Larsen Henrik J. Ditzel |
| author_facet | Sanne Løkkegaard Daniel Elias Carla L. Alves Martin V. Bennetzen Anne-Vibeke Lænkholm Martin Bak Morten F. Gjerstorff Lene E. Johansen Henriette Vever Christina Bjerre Tove Kirkegaard Bo Nordenskjöld Tommy Fornander Olle Stål Linda S. Lindström Laura J. Esserman Anne E. Lykkesfeldt Jens S. Andersen Rikke Leth-Larsen Henrik J. Ditzel |
| author_sort | Sanne Løkkegaard |
| collection | DOAJ |
| description | Abstract Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients. |
| first_indexed | 2024-03-11T14:10:33Z |
| format | Article |
| id | doaj.art-c7b5ad6a5a674cfcb8ece9f12b5c68d6 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-11T14:10:33Z |
| publishDate | 2021-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-c7b5ad6a5a674cfcb8ece9f12b5c68d62023-11-02T00:12:03ZengNature Portfolionpj Breast Cancer2374-46772021-01-017111510.1038/s41523-020-00210-8MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefitSanne Løkkegaard0Daniel Elias1Carla L. Alves2Martin V. Bennetzen3Anne-Vibeke Lænkholm4Martin Bak5Morten F. Gjerstorff6Lene E. Johansen7Henriette Vever8Christina Bjerre9Tove Kirkegaard10Bo Nordenskjöld11Tommy Fornander12Olle Stål13Linda S. Lindström14Laura J. Esserman15Anne E. Lykkesfeldt16Jens S. Andersen17Rikke Leth-Larsen18Henrik J. Ditzel19Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkCenter of Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Surgical Pathology, Zealand University HospitalDepartment of Pathology, Odense University HospitalDepartment of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Oncology, Copenhagen University HospitalCell Death and Metabolism, Danish Cancer Society Research CenterDepartment of Clinical and Experimental Medicine, Division of Oncology, Linköping UniversityDepartment of Oncology, Karolinska University HospitalDepartment of Clinical and Experimental Medicine, Division of Oncology, Linköping UniversityDepartment of Biosciences and Nutrition, Karolinska InstitutetDepartment of Surgery, UCSF Carol Franc Buck Breast Care Center, University of California, San FranciscoCell Death and Metabolism, Danish Cancer Society Research CenterCenter of Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkDepartment of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern DenmarkAbstract Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.https://doi.org/10.1038/s41523-020-00210-8 |
| spellingShingle | Sanne Løkkegaard Daniel Elias Carla L. Alves Martin V. Bennetzen Anne-Vibeke Lænkholm Martin Bak Morten F. Gjerstorff Lene E. Johansen Henriette Vever Christina Bjerre Tove Kirkegaard Bo Nordenskjöld Tommy Fornander Olle Stål Linda S. Lindström Laura J. Esserman Anne E. Lykkesfeldt Jens S. Andersen Rikke Leth-Larsen Henrik J. Ditzel MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit npj Breast Cancer |
| title | MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit |
| title_full | MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit |
| title_fullStr | MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit |
| title_full_unstemmed | MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit |
| title_short | MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit |
| title_sort | mcm3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit |
| url | https://doi.org/10.1038/s41523-020-00210-8 |
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