Characterization of Gene Expression in Human Breast Tumor Endothelium; Annual summary rept. 1 May 2007-30 Apr 2008

摘要

Angiogenesis is the growth of new capillary blood vessels, and is a critical component of solid tumor growth. We characterized molecular changes between human breast tumor vessels and normal vessels to identify genes that may serve as therapeutic targets. We developed a method for rapid immunohistochemistry (IHC) and laser capture microdissection (LCM) of vascular cells from frozen human breast tumors and normal breast tissue for genomic analysis. We found SFRP2 to have 6 fold increased mRNA expression in breast tumor vessels, and confirmed localization of SFRP2 to endothelium using IHC with antibodies to SFRP2 on paraffin-embedded breast tumors. SFRP2 protein expression in endothelium was significantly higher in breast tumors than normal (13/15 or 87% versus 4/10 or 40%, p=0.03). We found that SFRP2 stimulates angiogenesis ex vivo and in vitro through a calcineurin/ NFAT pathway. A polyclonal antibody to SFRP2 inhibited malignant endothelial tube formation, demonstrating the contribution of SFRP2 to angiogenesis. We found that tacrolimus, a calcineurin/ NFAT inhibitor inhibits SFRP2 induced endothelial tube formation, and inhibited malignant endothelial tumor growth in mice. Based on its expression and function, we have discovered that SFRP2 is a novel therapeutic target for the treatment of breast cancer.