Abstract
Matrix Metallopeptidase 1 (MMP-1) expression has repeatedly been correlated to tumorigenesis and metastasis. Yet, MMP-1 regulation in a metastatic context remains largely unknown. Here we confirm differential MMP-1 expression in mammary carcinoma cells with varied metastatic potentials. We show that MMP-1 expression is regulated by an AP-1 element in its promoter in highly metastatic MDA-MB-231 mammary carcinoma cell derivatives. Fra-1, an AP-1 family transcription factor, differentially binds this element in highly metastatic cells compared to low metastatic cells and is required for MMP-1 expression. Overexpression of Fra-1 also caused increased MMP-1 expression. Fra-1 mRNA levels are unchanged in the cell variants, however its protein levels are higher in the metastatic cells. While there was no change in Fra-1 protein degradation rates, protein synthesis of Fra-1 was increased in the metastatic cell variant. These results demonstrate that Fra-1 and MMP-1 levels are differentially regulated in metastatic cell variants at the level of Fra-1 protein translation. Consistent with the importance of Fra-1 for tumor growth, we found that Fra-1 overexpression was sufficient to increase cell motility and anchorage independent growth. These results suggest that increased Fra-1 translation is critical for regulation of MMP-1 and tumor cell metastasis.
Highlights
Matrix metallopeptidase-1 (MMP-1) expression is highly correlated to several forms of cancer[1]
There was no significant difference in protein expression levels of Fra-2, JunD or c-Jun. These results suggest the possibility that differences in Fra-1 protein expression in Scp-2, Scp-21 and MDA-MB-231 cell lines are responsible for regulation of MMP-1 transcription
We found that Fra-1 protein was more abundant in Scp-2 than Scp-21 cells, as previously seen, and when we normalized to the starting relative levels in each cell line, we found that there was no significant difference in the stability of Fra-1 in these two cell lines (Figure 7B, and Data File 7)
Summary
Matrix metallopeptidase-1 (MMP-1) expression is highly correlated to several forms of cancer[1]. MMP-1 expression has been correlated to primary tumor progression, metastatic potential, and survival[2,3,4,5,6]. In glioblastoma, melanoma and breast cancer, higher incidence has been associated with a single nucleotide polymorphism in an Ets-binding site which increases MMP-1 expression[7,8]. MMP-1 expression has been measured in a variety of breast cancer cell lines. MDAMB-231 cell variants with different metastatic potentials demonstrate the correlation between MMP-1 expression and metastasis[12,13,14]
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