Title: Regulation of Matrix Metallopeptidase-1 in Breast Cancer Metastasis
Description: 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 and identify a mechanism differentially regulating MMP-1. 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 derivatives compared to low-metastatic cells and is required for MMP1 expression. Fra-1 mRNA levels are unchanged in the cell variants, however its protein levels are higher in the metastatic cells. There was no change in protein degradation rates, while protein synthesis rates of Fra-1 increased. These results suggest that protein translation of Fra-1 is differentially regulated in these cells. Consistent with the importance of Fra-1 for tumor growth, we found that Fra-1 overexpression is sufficient to increase cell motility and anchorage independent growth. These results suggest that Fra-1 regulation is critical for regulation of MMP-1 and metastasis.