Basal-like carcinomas comprise 10-15% of the six breast cancer subtypes, and include those that are 'triple negative'(lacking ER-alpha, PR and HER2 expression), denoting clinically poor prognosis with few treatment options. The mesenchymal cell adhesion molecule, cadherin-11 is expressed only in poorly differentiated, highly invasive basal-like cells and is absent in normal breast epithelium and well-differentiated breast cancer cells. Preliminary data shows that cadherin-11 is commonly increased as an early event in a subset of human breast cancers and ductal carcinomas in-situ and is also elevated in CNS tumors and those of the GI system. Unlike HER2 positive breast cancers for which small molecule and antibody treatment is quite effective;there are no targeted therapies for highly aggressive tumors such as basal-like breast cancer and glioblastomas. However, cadherin-11 is a therapeutic target in the inflammatory disease rheumatoid arthritis (RA) and we found that cadherin-11 monoclonal antibodies, humanized versions of which will shortly be in clinical trials for RA, inhibited the growth of aggressive basal-like breast cancer xenografts in mice. Cadherin-11 attenuation also decreased tumorigenesis, proliferation, colony formation and migration of MDA-MB-231 basal-like breast cancer cells and LN229 glioblastoma cells. These data directly demonstrate that cadherin-11 is a bona-fide therapeutic target in inflammatory diseases such as RA and cancer and prompted us to develop small molecule inhibitors that specifically inhibit the growth and migration of cadherin-11 positive cells. We also found that cadherin-11 regulates CCL2 and other inflammatory mediators and growth regulatory pathways in both RA and cancer cells and further indicates that "some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?" as posited in Provocative Question 5. The proposal will combine the activities of the Cancer Biology and Drug Discovery Group that first described the role of cadherin-11 in breast cancer (Byers, Georgetown), the Rheumatology Group that discovered the role of cadherin-11 in this disease (Brenner, Harvard) and the Structural Biology Group that first determined the crystal structure of cadherin-11 (Shapiro, Columbia). Together we have the following aims. 1. To reposition approved drugs as cadherin-11 inhibitors. Preliminary in silico repositioning identified the anti- inflammatory drug, celecoxib as a cadherin-11 inhibitor. 2. Determine the role of CCL2 and other cadherin-11 regulated genes in mediating its effects on tumorigenesis, invasion and metastasis. 3. Determine the role of tyrosine kinase activation in mediating cadherin-11 signaling.
Basal-like breast cancers and brain tumors of the glioblastoma type are among the poorest prognosis cancers with no effective treatments. This proposal links a molecular pathway elevated in these tumors to a similar pathway important in the inflammatory disease rheumatoid arthritis. We propose that drugs currently in use for arthritis as well as drugs repurposed to inhibit the common pathway will be useful as novel cancer therapies.
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