Metastasis is a complicated process that depends largely on the interaction of primary tumors and the local host environment. In this study, we have established a new mouse model to mimic the process of tumor metastasis in breast cancer patients. TM40D-MB mouse mammary tumor cells were transplanted to the mammary glands of syngeneic mice. Mammary tumors developed in the glands in situ and were metastatic to bone with over 53% efficiency. We compared the gene expression profile of high (TM40D-MB) vs. low metastatic (TM40D) tumor cells using Affymetrix microarray chips. Microarray analysis revealed a list of genes that were consistently up-/down-regulated in TM40D-MB tumor cells. One of the genes, COX2 was selected for functional study. Injection of TM40D-COX2 cells to mouse femur caused a significant increase in bone destruction compared to TM40D-C control, as measured by the micro-computed tomography (μCT) scanning for the trabecular bone volume. In vitro assays showed that COX2 significantly increased the rate of osteoclast formation, and this effect was reversible by the specific COX2 inhibitor NS-398. These data indicate that COX2 is one gene important for breast cancer bone metastasis. The availability of this mouse model and the comparative study of gene expression signatures between TM40D and other bone metastasis models will likely generate important information about common pathways for breast cancer bone metastasis. Further functional studies of metastasis signature genes should help to develop means to curb the metastasis process.