Discoidin Domain Receptor 1 (DDR1): A Putative Suppressor of Intraosseous Breast Cancer Lesions

Nova Southeastern University, Davie, Florida, USA

Objective. To investigate the role of Discoidin Domain Receptor 1 (DDR1) in intraosseous growth of human MDA-MB-231 breast cancer (BrCa) cells. Background. BrCa commonly metastasizes to bone in women with advanced disease, leading to high morbidity and reduced survival. Treatments available for these patients are palliative, but not curative. DDRs represent the only receptor tyrosine kinases that signal in response to collagen, the major organic component of bones. Although DDR1 -one of the two DDR forms- is expressed in invasive BrCa, its contribution to bone metastasis remains unexplored. Methods. MDA-MB-231 cells were engineered to express either wild-type (WT) or kinase-dead (KD) inactive DDR1, or no DDR1 (Empty vector:EV). Western blot (WB) was used to assess DDR expression and activation. Cells were inoculated into the tibiae of female athymic nude mice. Three weeks later, tibiae were harvested and processed for H&E staining and immunohistochemistry of cytokeratins (epithelial marker) to identify BrCa cells within the bone. Histomorphometry analysis was performed to measure tumor and bone areas on the entire tibiae. Results. WB analysis showed expression of DDR1 in WT and KD but not in EV MDA-MB-231 cells. WT- but not KD-DDR1 was activated by collagen. Histomorphometrical analyses revealed that WT-DDR1 cells formed smaller intraosseous tumors than EV cells, whereas KD-DDR1 cells produced significantly larger tumors (pConclusion. These results suggest that DDR1 plays a tumor-suppressing role in BrCa cells residing within the bone niche that is dependent on its tyrosine kinase activity.