Cyclooxygenase-2-derived prostaglandin E₂ stimulates Id-1 transcription

Cyclooxygenase-2 (COX-2) and Id-1 are overexpressed in a variety of human malignancies. Recently, each of these genes was found to play a role in mediating breast cancer metastasis to the lungs, but their potential interdependence was not evaluated. Hence, the main objective of the current study was to determine whether COX-2-derived prostaglandin (PGE₂) activated Id-1 transcription, leading in turn to increased invasiveness of mammary epithelial cells. In MDA-MB-231 cells, treatment with PGE₂ induced Id-1, an effect that was mimicked by an EP₄ agonist. PGE ₂ via EP₄ activated the epidermal growth factor receptor (EGFR) → ERK1/2 pathway, which led to increased expression of Egr-1. PGE₂ stimulated EGFR signaling by inducing the release of amphiregulin, an EGFR ligand. The ability of PGE₂ to activate Id-1 transcription was mediated by enhanced binding of Egr-1 to the Id-1 promoter. Silencing of COX-2 or pharmacological inhibition of COX-2 led to reduced PGE₂ production, decreased Id-1 expression, and reduced migration of cells through extracellular matrix. A similar decrease in cell migration was found when Id-1 was silenced. The interrelationship between COX-2, PGE ₂, Id-1, and cell invasiveness was also compared in nontumorigenic SCp2 and tumorigenic SCg6 mammary epithelial cells. Consistent with the findings in MDA-MB-231 cells, COX-2-derived PGE₂ induced Id-1, leading in turn to increased cell invasiveness. Taken together, these results suggest that PGE₂ via EP₄ activated the EGFR→ ERK1/2 → Egr-1 pathway, leading to increased Id-1 transcription and cell invasion. These findings provide new insights into the relationship between COX-2 and Id-1 and their potential role in metastasis.