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.