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| Status |
Public on Nov 17, 2020 |
| Title |
The effect of MCM3 gene knockdown on gene expression profile of tamoxifen-resistant breast cancer cell lines |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
MCM3 is one of several genes whose expression profile is markedly altered in tamoxifen-resistant breast cancer cell lines. We observed that increased MCM3 expression is associated with tamoxifen resistance. Knockdown of MCM3 resulted in increased susceptibility of tamoxifen-resistant breast cancer cell lines. Moreover, MCM3 expression is significantly associated with clinical outcome of endocrine treated receptor positive breast cancer. To understand the effect of MCM3 on the mechanism of endocrine resistance, we performed gene expression array on tamoxifen-resistant breast cancer cell lines. Here we show that MCM3 knockdown affects the expression of hundreds of genes.
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 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. 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 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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| Overall design |
The experiment involved three tamoxifen-resistant and 1 tamoxifen-sensitive MCF7 cell lines. MCM3 gene knockdown was performed by transfecting cells with gene specific siRNA and control siRNA. The effect of MCM3 gene knockdown on global gene expression profile was assessed by performing gene array using HG-U133_Plus_2 Affymetrix array platform.
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| Contributor(s) |
Løkkegaard S, Elias D, Bennetzen MV, Lænkholm A, Bak M, Gjerstorff MF, Johansen LE, Vever H, Bjerre C, Kirkegaard T, Nordenskjold B, Formander T, Stål O, Lindström LS, Esserman LJ, Lykkesfeldt AE, Andersen JS, Leth-Larsen R, Ditzel HJ |
| Citation(s) |
33398005 |
| Submission date |
Apr 17, 2020 |
| Last update date |
Jan 19, 2021 |
| Contact name |
Henrik Ditzel |
| E-mail(s) |
hditzel@health.sdu.dk
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| Organization name |
University of Southern Denmark
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| Street address |
J.B. Winsløwsvej 25
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| City |
Odense |
| State/province |
Denmark |
| ZIP/Postal code |
5000 |
| Country |
Denmark |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA626012 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE148878_RAW.tar |
36.5 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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