Roles of the cyclooxygenase 2-matrix metalloproteinase 1 pathway in brain metastasis of breast cancer [Signal Transduction]

February 17th, 2015 by Wu, K., Fukuda, K., Xing, F., Zhang, Y., Sharma, S., Liu, Y., Chan, M., Zhou, X., Qasem, S., Pochampally, R., Mo, Y.-Y., Watabe, K.

Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of critical rate limiting steps of brain metastasis is the breaching the blood-brain barrier (BBB) which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only MMP1 is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1 that are key components of BBB. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, while ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins (PGs) were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release Chemokine (C-C motif) ligand 7 (CCL7) which in turn promoted self-renewal of tumor initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.