MDM2 promotes invasion and metastasis in invasive ductal breast carcinoma by inducing matrix metalloproteinase-9
Open accessAbstract
The molecular mechanisms that underpin invasive ductal breast cancer (IDC) invasion and metastasis are incompletely understood. The oncogene, mouse double minute 2 (MDM2), has been implicated in the pathogenesis of numerous cancers, where it stimulates the expression of matrix metalloproteinase 9 (MMP9), an important enzyme in the breakdown of the extracellular matrix. However, its role in breast cancer remains poorly understood. This study assessed the clinical significance of MDM2 expression in IDC and used in vitro expression assays to determine the molecular roles of MDM2. Immunohistochemical staining for MMP9 and MDM2 was performed using archived tumor blocks from 321 women who underwent surgical resection for IDC at the First Affiliated Hospital of Nanjing Medical University, China between January 2002 and December 2003. MCF-7 and MDA-MD-231 cell lines were transfected with siRNA targeted against MDM2, or MDM2 was overexpressed using transiently expressed vectors. The invasion, cell migration and proteolytic capabilities of cells that over- or underexpressed MDM2 was then assessed and compared against control cells, in addition to the consequent effects on MMP9 expression using RT-PCR. In vivo, 54.9% and 49.6% of samples were positive for MMP9 and MDM2 expression, respectively, and their expression was significantly correlated (r² = 0.171, P = 0.012). Moreover, MDM2 expression was markedly correlated with disease-free survival (HR 2.56, 95% CI 1.02-6.40, P = 0.038). In vitro, MDM2 overexpression significantly enhanced cell invasion, migration and proteolysis compared with control cells, and the converse effects were observed after MDM2-siRNA treatment. MDM2 overexpression induced MMP9 expression in a dose-dependent manner. Taken together, these results suggest that high levels of MDM2 are associated with a poorer prognosis in IDC. This might result from increased tumor invasiveness due to enhanced MMP9 expression causing increased extracellular matrix breakdown.
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High Mdm2 levels correlate with a higher incidence of metastasis in vivo.
“Moreover, evidence suggests that high Mdm2 levels correlate with a higher incidence of metastasis in vivo (6, 8, 9).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [9]
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- Authors
- Chen, X., Qiu, J., Yang, D., Lu, J., Yan, C., Zha, X., & Yin, Y.
- Affiliations
- Jiangsu Province Hospital (CN)
- Corresponding author
- Zha, Xiaoming
- Yin, Yongmei
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-11-13
- Volume
- 8
- Issue
- 11
- Pages
- e78794
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3827260
- OpenAlex
- W2058088175
- Cited by
- 47
- References
- 45
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 5 · 2021: 1 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 8 · 2015: 10 · 2014: 4
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (2012008, 81172503)
- Government of Jiangsu Province
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- MDM2, MMP-9, invasive ductal carcinoma, breast cancer, tumor invasion, metastasis, extracellular matrix degradation, cell migration, prognosis, disease-free survival, siRNA knockdown, MDM2 overexpression
- MeSH terms
- Adult, Aged, Breast Neoplasms, Enzyme Induction, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoplasm Invasiveness, Promoter Regions, Genetic, Up-Regulation, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Proportional Hazards Models, Carcinoma, Ductal, Breast, Disease-Free Survival, Matrix Metalloproteinase 9, Tumor Burden, Proto-Oncogene Proteins c-mdm2, Young Adult, MCF-7 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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