A wide range of genes involved in breast cancer metastasis have been reported to be related to the microenvironment. We studied the role of discoidin domain receptor 2 (DDR2), a collagen-binding receptor, in breast cancer progression under hypoxic conditions. We showed that DDR2 protein expression closely correlated with the expression of hypoxic marker HIF-1α in clinical breast cancer specimens. The in vitro data demonstrated that hypoxia treatment increased the levels of both expression and phosphorylation of DDR2 in human breast cancer cell lines. In vivo, orthotopic breast tumour xenografts with DDR2 knockdown displayed reduced dissemination and significant prevention in pulmonary and lymphatic metastasis; conversely, these processes were significantly facilitated by the enforced expression of the activated form of DDR2. Further mechanism studies indicated that DDR2 plays an indispensable role in a series of hypoxia-induced behaviours of breast cancer cells, including migration, invasion, and epithelial-mesenchymal transition (EMT). The transcription factor Snail was found to mediate DDR2-induced down-regulation of the cell-cell adhesion molecule E-cadherin. It was also documented that there is a correlation between DDR2 and E-cadherin expression with the presence of lymph node metastases in 160 cases of invasive human breast carcinoma. In addition, we provided evidence that DDR2 silencing in breast cancer cells prevents the hypoxia-induced activation of ERK MAPK, suggesting its potential involvement in mediating the effect of DDR2 on hypoxia-induced signalling. Based on the results of this study, we conclude that DDR2 participates in hypoxia-induced breast cancer metastasis through the regulation of cell migration, invasion, and EMT, and thus may serve as an accessible therapeutic target for the treatment of breast cancer.

Objective. Discoidin domain receptor 2 (DDR-2)/ matrix metalloproteinase (MMP) signaling is an important pathway involved in cartilage destruction in rheumatoid arthritis (RA). However, the molecular mechanisms of this pathway have not been clearly identified. This study was undertaken to screen key molecules involved in this pathway and evaluate their biologic functions in synovium invasion of RA.Methods. DDR-2-interacting proteins were examined in vitro by immunoprecipitation and mass spectrometry, and annexin A2 was acquired. The effects of annexin A2 on fibroblast-like synoviocyte (FLS) migration were evaluated using a Transwell invasion assay and an Erasion trace test. In Ddr2 ؊/؊ mice with collagen-induced arthritis (CIA), hematoxylin and eosin (H&E) staining, immunohistochemical analysis, and Western blot analysis were used to assess expression of DDR-2, annexin A2, and MMP-13, as well as synovial hyperplasia. Rats with CIA were treated with lentivirus annexin A2 small interfering RNA (siRNA), and annexin A2 siRNA effects on joint damage were analyzed based upon arthritis index scores and results of micro-computed tomography and H&E staining. The differences between annexin A2 expression in clinical samples from RA and osteoarthritis patients were compared using Western blotting.Results. Annexin 2 was identified for the first time as a DDR-2 binding protein. It may be phosphorylated by phospho-DDR-2, leading to MMP-13 secretion. The annexin A2 phosphorylation level and MMP-13 expression level were decreased and collagen-induced joint damage greatly reduced in Ddr2 ؊/؊ mice. Joint damage in rats with CIA was significantly ameliorated when annexin A2 was down-regulated. Annexin A2 expression and phosphorylation were elevated in human RA synovial tissue.

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