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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c7b5ad6a5a674cfcb8ece9f12b5c68d6
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spelling	oai:doaj.org-article:c7b5ad6a5a674cfcb8ece9f12b5c68d62021-12-02T15:16:17ZMCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit10.1038/s41523-020-00210-82374-4677https://doaj.org/article/c7b5ad6a5a674cfcb8ece9f12b5c68d62021-01-01T00:00:00Zhttps://doi.org/10.1038/s41523-020-00210-8https://doaj.org/toc/2374-4677Abstract 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.Sanne LøkkegaardDaniel EliasCarla L. AlvesMartin V. BennetzenAnne-Vibeke LænkholmMartin BakMorten F. GjerstorffLene E. JohansenHenriette VeverChristina BjerreTove KirkegaardBo NordenskjöldTommy FornanderOlle StålLinda S. LindströmLaura J. EssermanAnne E. LykkesfeldtJens S. AndersenRikke Leth-LarsenHenrik J. DitzelNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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
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.
format	article
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
title	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_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_sort	mcm3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c7b5ad6a5a674cfcb8ece9f12b5c68d6
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MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

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