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MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit
- Source :
- NPJ breast cancer, vol 7, iss 1, Løkkegaard, S, Elias, D, Alves, C L, Bennetzen, M V, Lænkholm, A-V, Bak, M, Gjerstorff, M F, Johansen, L E, Vever, H, Bjerre, C, Kirkegaard, T, Nordenskjöld, B, Fornander, T, Stål, O, Lindström, L S, Esserman, L J, Lykkesfeldt, A E, Andersen, J S, Leth-Larsen, R & Ditzel, H J 2021, ' MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit ', npj Breast Cancer, vol. 7, no. 1, pp. 2 . https://doi.org/10.1038/s41523-020-00210-8, npj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021), NPJ Breast Cancer, Løkkegaard, S, Elias, D, Alves, C L, Bennetzen, M V, Lænkholm, A V, Bak, M, Gjerstorff, M F, Johansen, L E, Vever, H, Bjerre, C, Kirkegaard, T, Nordenskjöld, B, Fornander, T, Stål, O, Lindström, L S, Esserman, L J, Lykkesfeldt, A E, Andersen, J S, Leth-Larsen, R & Ditzel, H J 2021, ' MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit ', npj Breast Cancer, vol. 7, 2 . https://doi.org/10.1038/s41523-020-00210-8
- Publication Year :
- 2021
- Publisher :
- Linköpings universitet, Avdelningen för kirurgi, ortopedi och onkologi, 2021.
-
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(Ser(315,33)), CHK1(Ser(317)), and cdc25b(Ser(323)), 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. Funding Agencies|Danish Cancer SocietyDanish Cancer Society; Danish Cancer Research Foundation; Danish Research CouncilDet Frie Forskningsrad (DFF); Danish Strategic Research CouncilDanske Strategiske Forskningsrad (DSF); A Race Against Breast Cancer; Region of Southern Denmark Research Foundation; Odense University Hospital Research Council
- Subjects :
- 0301 basic medicine
medicine.drug_class
Predictive markers
Article
03 medical and health sciences
0302 clinical medicine
Breast cancer
Downregulation and upregulation
Breast Cancer
Medicine
Endocrine system
Pharmacology (medical)
Radiology, Nuclear Medicine and imaging
RC254-282
Cancer
screening and diagnosis
Cancer och onkologi
Predictive marker
business.industry
Letrozole
Evaluation of treatments and therapeutic interventions
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Cell cycle
medicine.disease
Estrogen
Detection
Mechanisms of disease
030104 developmental biology
Oncology
5.1 Pharmaceuticals
6.1 Pharmaceuticals
030220 oncology & carcinogenesis
Cancer and Oncology
Cancer research
Development of treatments and therapeutic interventions
business
Tamoxifen
4.2 Evaluation of markers and technologies
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- NPJ breast cancer, vol 7, iss 1, Løkkegaard, S, Elias, D, Alves, C L, Bennetzen, M V, Lænkholm, A-V, Bak, M, Gjerstorff, M F, Johansen, L E, Vever, H, Bjerre, C, Kirkegaard, T, Nordenskjöld, B, Fornander, T, Stål, O, Lindström, L S, Esserman, L J, Lykkesfeldt, A E, Andersen, J S, Leth-Larsen, R & Ditzel, H J 2021, ' MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit ', npj Breast Cancer, vol. 7, no. 1, pp. 2 . https://doi.org/10.1038/s41523-020-00210-8, npj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021), NPJ Breast Cancer, Løkkegaard, S, Elias, D, Alves, C L, Bennetzen, M V, Lænkholm, A V, Bak, M, Gjerstorff, M F, Johansen, L E, Vever, H, Bjerre, C, Kirkegaard, T, Nordenskjöld, B, Fornander, T, Stål, O, Lindström, L S, Esserman, L J, Lykkesfeldt, A E, Andersen, J S, Leth-Larsen, R & Ditzel, H J 2021, ' MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit ', npj Breast Cancer, vol. 7, 2 . https://doi.org/10.1038/s41523-020-00210-8
- Accession number :
- edsair.doi.dedup.....b98ea350b249a8cffb0597a2fbcc9544