2. Academic Validation
  3. MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

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

  • NPJ Breast Cancer. 2021 Jan 4;7(1):2. doi: 10.1038/s41523-020-00210-8.
Sanne Løkkegaard 1,  Daniel Elias 1,  Carla L Alves 1,  Martin V Bennetzen 2,  Anne-Vibeke Lænkholm 3,  Martin Bak 4,  Morten F Gjerstorff 1,  Lene E Johansen 1,  Henriette Vever 1,  Christina Bjerre 5,  Tove Kirkegaard 6,  Bo Nordenskjöld 7,  Tommy Fornander 8,  Olle Stål 7,  Linda S Lindström 9,  Laura J Esserman 10,  Anne E Lykkesfeldt 6,  Jens S Andersen 2,  Rikke Leth-Larsen 1 11,  Henrik J Ditzel 12 13 14
Affiliations

Affiliations

  • 1 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DK-5000, Denmark.
  • 2 Center of Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK-5230, Denmark.
  • 3 Department of Surgical Pathology, Zealand University Hospital, Roskilde, DK-4000, Denmark.
  • 4 Department of Pathology, Odense University Hospital, Odense, DK-5000, Denmark.
  • 5 Department of Oncology, Copenhagen University Hospital, Rigshospitalet, DK-2100, Copenhagen, Denmark.
  • 6 Cell Death and Metabolism, Danish Cancer Society Research Center, Copenhagen, DK-2100, Denmark.
  • 7 Department of Clinical and Experimental Medicine, Division of Oncology, Linköping University, Linköping, SE-58185, Sweden.
  • 8 Department of Oncology, Karolinska University Hospital, Stockholm, SE-11883, Sweden.
  • 9 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, SE-14183, Sweden.
  • 10 Department of Surgery, UCSF Carol Franc Buck Breast Care Center, University of California, San Francisco, San Francisco, 94115, CA, USA.
  • 11 Department of Regional Health Research, University of Southern Denmark, Odense, DK-5000, Denmark.
  • 12 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DK-5000, Denmark. hditzel@health.sdu.dk.
  • 13 Department of Oncology, Odense University Hospital; Department of Clinical Research, University of Southern Deanmark, Odense, DK-5000, Denmark. hditzel@health.sdu.dk.
  • 14 Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense, DK-5000, Denmark. hditzel@health.sdu.dk.
PMID: 33398005 DOI: 10.1038/s41523-020-00210-8
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.

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