Abstract
Cadherin-11 (CDH11), associated with epithelial to mesenchymal transformation in development, poor prognosis malignancies and cancer stem cells, is also a major therapeutic target in rheumatoid arthritis (RA). CDH11 expressing basal-like breast carcinomas and other CDH11 expressing malignancies exhibit poor prognosis. We show that CDH11 is increased early in breast cancer and ductal carcinoma in-situ. CDH11 knockdown and antibodies effective in RA slowed the growth of basal-like breast tumors and decreased proliferation and colony formation of breast, glioblastoma and prostate cancer cells. The repurposed arthritis drug celecoxib, which binds to CDH11, and other small molecules designed to bind CDH11 without inhibiting COX-2 preferentially affect the growth of CDH11 positive cancer cells in vitro and in animals. These data suggest that CDH11 is important for malignant progression, and is a therapeutic target in arthritis and cancer with the potential for rapid clinical translation.
Highlights
Poor prognosis epithelial-derived cancers often exhibit morphologic and molecular changes characteristic of an epithelial to mesenchymal transition (EMT) and EMT markers are predominantly found in tumors with a basal-like phenotype [1;2]
To more formally test the association of CDH11 with poor prognosis malignancies we first carried out a meta-analysis of all published datasets to show that in addition to being elevated in early stages of breast cancer such as ductal carcinoma in-situ (DCIS), CDH11 is highly expressed in gastrointestinal, brain and central nervous system tumors
The work presented here confirms the association of CDH11 with a number of malignancies and demonstrates that CDH11 is an important driver of certain poor prognosis cancers, as it is in rheumatoid arthritis (RA)
Summary
Poor prognosis epithelial-derived cancers often exhibit morphologic and molecular changes characteristic of an epithelial to mesenchymal transition (EMT) and EMT markers are predominantly found in tumors with a basal-like phenotype [1;2]. CDH11 is expressed only in poorly differentiated, highly-invasive cells [5]. All CDH11 positive cell lines are in the basal B subset of poor prognosis breast cancer cells [3]. To more formally test the association of CDH11 with poor prognosis malignancies we first carried out a meta-analysis of all published datasets to show that in addition to being elevated in early stages of breast cancer such as ductal carcinoma in-situ (DCIS), CDH11 is highly expressed in gastrointestinal, brain and central nervous system tumors. We showed previously that the arthritis drug celecoxib had the structural potential to bind this pocket and show that celecoxib, a celecoxib analogue with no COX-2 inhibitory activity, as well as several novel small molecules can selectively inhibit the growth of CDH11 expressing breast cancer cells [7]
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