CADHERIN-11 MEDIATION OF TUMOR PROGRESSION AND INVASION IN POOR PROGNOSIS CANCERS: A VIABLE THERAPEUTIC TARGET

Abstract

Loss of E-cadherin is considered a hallmark of epithelial carcinogenesis and has been well-studied to date. Likewise, increases in N-cadherin are known to lead to tumor progression and metastasis in various cancers. A lesser studied cadherin in cancer, cadherin-11, has also been associated with migratory potential and invasion throughout development and tumorigenesis. Cadherin-11, which bears multiple similarities to N-cadherin, is a type II mesenchymal cadherin known to be up-regulated in certain epithelial cancers, including basal-like breast carcinoma and advanced prostate cancer, and invasive cell lines, yet is absent in normal epithelium. Our lab previously reported that cadherin-11 is expressed only in invasive breast cancer cell lines, and addition of exogenous cadherin-11 to non-metastatic SKBR3 cells significantly increases their ability to migrate. We now show that stable reduction of cadherin-11, via RNAi interference, in aggressive MDA-MB-231 breast cancer cells and PC-3 prostate cancer cells results in dramatic and significant decreases in proliferation, migration, and invasion potentials. Furthermore, cadherin-11 depletion in these metastatic cells prevents tumor growth in mice and alters the expression of genes associated with poor prognosis malignancies. A novel small molecule inhibitor designed to target its unique adhesive interface significantly and specifically inhibits the growth and migration of cadherin-11 positive cells. These results suggest that cadherin-11 is essential for malignant progression of MDA-MB-231 breast and PC-3 prostate cancer cells, and potentially other aggressive cancers as well. Furthermore, the data collectively imply that cadherin-11 may serve as both a marker for more aggressive tumors as well as a viable therapeutic target for breast carcinomas that express its protein. Although cadherin-11 expressing basal-like breast carcinomas constitutes only 10-15% of known breast cancers they are those with clinically poor prognosis and few treatment options. This study shows that blockade of cadherin-11, either by knockdown or using a new drug-like small molecule inhibitor, inhibits malignant progression of MDA-MB-231 basal-type cells and indicates that cadherin-11 may be a therapeutic target for poor prognosis carcinomas.