Activating transcription factor‐2 (ATF2) mediates MMP‐2 transcriptional activation induced by p38 MAPK in breast epithelial cells

Abstract

Mounting evidence suggests a role for matrix metalloproteinase (MMP)-2 in the malignant progression of breast cancer cells. We previously showed that H-Ras, but not N-Ras, induced invasion and migration of MCF10A human breast epithelial cells through H-Ras-specific activation of Rac-MKK3/6-p38 MAPK pathway resulted in MMP-2 up-regulation. In this study, we aimed to elucidate the transcriptional regulation of MMP-2 by p38 MAPK pathway leading to the invasive and migrative phenotypes of MCF10A breast epithelial cells. By using 5′ deletion mutant constructs of MMP-2 promoter, we showed that the AP-1 binding site is critical for the MMP-2 promoter activation in MKK6- and H-Ras-activated MCF10A cells. DNA binding and transcriptional activities of AP-1 were increased by MKK6 or H-Ras. We revealed the activating transcription factor (ATF)2 as a transcription factor for MMP-2 gene expression through binding to the functional AP-1 site. Activation of ATF2 by MKK6 or H-Ras was crucial for MMP-2 promoter activity as well as induction of invasive and migrative phenotypes in MCF10A cells. This is the first report revealing ATF2 as an essential transcription factor linking MKK3/6-p38 MAPK signaling pathway to MMP-2 up-regulation, providing evidence for a direct role of ATF2 activation in malignant phenotypic changes of human breast epithelial cells. [Supported by a grant (R01-2005-000-10596-0) from Korea Science & Engineering Foundation]