PLoS One. 2013 Nov 13;8(11):e78794. doi: 10.1371/journal.pone.0078794. eCollection 2013.
MDM2 promotes invasion and metastasis in invasive ductal breast carcinoma by inducing matrix metalloproteinase-9.
Abstract
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.
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.
- PMID:
- 24236052
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3827260
