期刊
BREAST CANCER RESEARCH AND TREATMENT
卷 82, 期 2, 页码 75-82出版社
KLUWER ACADEMIC PUBL
DOI: 10.1023/B:BREA.0000003948.14026.7c
关键词
collagen; ERK; invasion/metastasis; MAPK; matrix metalloproteinase; signal transduction
类别
资金
- NCI NIH HHS [CA-77267] Funding Source: Medline
- NIAMS NIH HHS [AR-26599] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA077267] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R37AR026599, R01AR026599] Funding Source: NIH RePORTER
Degradation of stromal collagens in the extracellular matrix is mediated largely by matrix metalloproteinase-1 (MMP-1; collagenase-1), and high constitutive levels of MMP-1 in breast cancer correlate with a poor prognosis and invasive disease. MMP-1 expression is, in part, controlled by the mitogen-activated protein kinase (MAPK) pathway(s), which may target several activator protein-1 (AP-1) and polyoma enhancing activity-3/E26 virus (PEA3/ETS) sites within the promoter. An additional ETS site in the MMP-1 promoter is conferred by a single nucleotide polymorphism (SNP) at - 1607 bp, when two guanines (5'-GGAT-3'; '2G allele/SNP') are present instead of one guanine (5'-GAT-3'; '1G allele/SNP'). This SNP is adjacent to an AP-1 site at - 1602 bp, and in the presence of the 2G allele (ETS site), these sites cooperate to induce higher levels of transcription. ERK 1/2 is one component of the MAPK pathway and is constitutively active in MCF-7/ADR breast cancer cells, which are 1G/2G heterozygotes. This study demonstrates that when these cells are treated with PD098059, an ERK-specific inhibitor, MMP-1 mRNA levels are significantly decreased, suggesting that high constitutive expression of MMP-1 in these cells results from continuous ERK 1/2 activation. Using transient transfection, we determined that this signaling pathway targets different AP-1/ETS sites, depending upon which allele is present. Furthermore, in these cells, the AP-1 site at - 1602 bp enhances transcription in the presence of the 2G SNP, but represses transcription from the 1G SNP. Finally, inhibiting ERK signaling and MMP-1 expression blocks type I collagen degradation and reduces the invasive ability of the MCF-7/ADR cells. We conclude that ERK 1/2 signaling and the 2G SNP mediate high levels of MMP-1 expression, which may contribute to the invasive potential of these breast cancer cells.
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