Specifically, COX-2 is upregulated by nuclear EGFR and synthesizes prostaglandins to directly upregulate the expression of matrix metalloproteinase-1 (MMP1) which in turn degrades the inter-endothelial tight junctions, occludin and claudin, increases the BBB permeability and promotes transendothelial migration of BC cells and brain metastasis [40]. The gene discussed is PTGS2; the disease is breast cancer.