MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

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*

*Kontaktforfatter for dette arbejde

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummer2
Tidsskriftnpj Breast Cancer
Vol/bind7
Antal sider15
ISSN2374-4677
DOI
StatusUdgivet - jan. 2021

Bibliografisk note

Funding Information:
We would like to thank Lisbet Mortensen and Ole Nielsen at the Department of Pathology, Odense University Hospital, for excellent technical assistance, and M. Kat Occhipinti for editorial assistance. This work was supported in part by the Danish Cancer Society, the Danish Cancer Research Foundation, the Danish Research Council, the Danish Strategic Research Council, A Race Against Breast Cancer, Region of Southern Denmark Research Foundation, and Odense University Hospital Research Council.

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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