Although basal-like breast carcinomas constitute only 10%-15% of known breast cancers, they are generally resistant to hormone therapy and have clinically poor prognosis. Loss of the epithelial cell-cell adhesion molecule E-cadherin is associated with poorly differentiated cancers. However, several studies have concluded that E-cadherin loss may be necessary but is not sufficient to promote invasion and metastasis. In fact, recent studies point to increased expression of another adhesion molecule, cadherin-11, as a far better predictor of the invasive and metastatic phenotype. Our analyses show that elevated cadherin-11 expression strikingly associates with poor survival in breast cancer and other poor prognosis malignancies. In recently submitted work, we show that cadherin-11 is actually required for the growth of basal-like breast tumors in mice. Blockade of cadherin-11, either by knockdown of its RNA or using a new drug-like small molecule inhibitor, inhibits malignant progression of MDA-231 basal-type cells and indicates that cadherin-11 may be a new therapeutic target for poor prognosis malignancies. It is our general goal to strengthen the notion that cadherin-11 constitutes a therapeutic target in poor prognosis breast cancer and to further develop and test reagents designed to inhibit its adhesive function. It is the specific goal of this grant to complete preclinical studies of cadherin-11 inhibitors with a view to moving them to the clinic shortly after the 2-year grant period is completed. Our aims are: (1) Move our lead compound into toxicity and efficacy studies in animals. (2) Test cadherin-11 function-blocking monoclonal antibodies in vitro and in animals. (3) Screen, synthesize, modify, and test second-generation small molecule cadherin-11 inhibitors. (4) Develop methods for the routine detection of cadherin-11 in human breast cancer with a view to identifying patients who are candidates for anti-cadherin-11 therapy.

Potential Impact: There remain significant sub-categories of breast cancer that are resistant to many therapies and remain essentially untreatable. If successful, this application will lead to the development of a new therapy for basal-like breast cancers and potentially other incurable malignancies.