Increased COX2 expression enhances tumor-induced osteoclastic lesions in breast cancer bone metastasis

Objective: Metastastic dissimination depends on interaction between tumor and local host environment. In this study, we established a new mouse model to mimic the process of bone metastasis in breast cancer. Methods: TM40D-MB mouse mammary tumor cells were transplanted to the mammary glands of mice causing local tumore metastatic to bone. We compared the expression of high (TM40D-MB) versus low metastatic (TM40D) tumor cells using the Affymetrix microarray platform. Differentially expressed genes were confirmed by Northern-blot analysis. The COX2 gene was selected for functional studies. TM40D-COX2 and TM40D-C control cells were injected to mouse femur and the effect was analyzed by Micro-CT scanning for trabecular bone volume. Shown effects were challenged by COX2 inhibition (NS–398) in an osteoclast formation assay.

Results: Mammary tumors developed and were metastatic to bone in 53%. Microarray analysis revealed differentially expressed genes which were confirmed by Northern-blot analysis. Injection of TM40D-COX2 cells to mouse femur caused increase in bone destruction compared to TM40D/TM40D-C. COX2 increased the rate of osteoclast formation in-vitro, which was reversible by NS–398.

Conclusion: COX2 expression can influence bone metastasis in this model. The comparative study of gene expression signatures between TM40D and other bone metastasis models will likely generate information about important pathways for breast cancer bone metastasis. Further functional studies of signature genes should help to develop means to curb the metastasis process. Clinical evaluation of specific COX2 inhibitors will clarify the use of these drugs in adjuvant and advanced disease treatment.

COX2 - gene-expression - osteoclast