P2-01-26: TIMPv: a novel downstream transcriptional target gene that underpins CD146-suppressed breast tumor invasion

Abstract

Abstract Background: CD146, a marker of endothelial cells, promotes tumor progression of many cancers including melanoma and prostate. Strikingly, several lines of evidence suggest that it is a suppressor of breast cancer (BC) progression. Not only the ligand(s) has not been identified, but CD146-downstream signaling mechanisms remain unknown. Material and Methods: Here, we report the functional importance of CD146 and that of a novel transcriptional target of CD146-signaling, variant of tissue inhibitor of metalloproteinases (TIMPv) identified by microarray analysis, in underpinning the suppression of BC invasion, using novel validated Enhanced Green Fluorescent Protein (EGFP)-inducible systems of CD146 expression both in vitro and in vivo. Results: In functional experiments, induction of CD146 inhibited BC cell migration and invasion. TIMPv was identified by expression profiling as a novel transcriptional target of CD146-signaling, an association validated by quantitative PCR and immunoblotting experiments in a range of breast and melanoma cancer cells. However, siRNA inhibition of CD146 in the SKMel-28 melanoma cell line increased TIMPv expression, suggesting that while TIMPv is a positive transcriptional target of CD146 in BC cells, it is negatively regulated in melanoma cells. Furthermore, the functional relevance of TIMPv to CD146-suppressed metastasis was demonstrated by selective suppression of TIMPv in CD146-expressing BC inducible cells using RNAi. More interestingly, induction of CD146 expression in vivo using mouse EGFP-inducible system of CD146 expression resulted in suppression of breast tumor growth. Discussion: Our study is the first report to provide a functional molecular link of TIMPv to cancer via unique axis that underpin CD146-suppressed BC progression, thus identifying TIMPv as a potential target for guiding the development of novel therapeutic strategies for BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-26.