The role of matriptase and its inhibitor HAI-1 in breast cancer growth, invasion, and metastasis

Matriptase is a type II transmembrane serine protease that might play a role in the progression of numerous types of cancer, including breast cancer. As an inhibitor of matriptase, hepatocyte growth factor activator inhibitor-1 (HAI-1) could prevent tumor progression. To determine whether matriptase expression, matriptase activity, or the matriptase-to-HAI-1 ratio correlates with tumor progression, the expression of matriptase and HAI-1 were examined both in normal human tissues and in primary human tumors and cultured cell lines. Matriptase protein levels in primary human tumors were similar to those found in normal human tissues. However, an increase in the level of the activated form of the enzyme was found in the absence of compensatory changes in HAI-1 in some breast tumor cells compared to surrounding normal breast epithelia, indicating that matriptase activity may be higher in tumor cells. In addition, a study of ovarian tumors of varying clinical stages indicated that the matriptase-to-HAI-1 protein level was more frequently elevated in later stage ovarian cancer.; To test the hypothesis that the matriptase-to-HAI-1 protein level in cultured breast cancer cells is directly involved in measures of tumor progression, inducible and stable over-expression systems were created for both matriptase and HAI-1 in MCF-7 and MDA MB-435 breast cancer cell lines, respectively. Both the MCF-7 and MDA MB-435 cell systems failed to show any effect of matriptase over-expression on measures of tumor progression such as in vitro cell growth, morphology, motility, and matrix degradation, or in vivo tumor growth, invasion, and metastasis. The over-expression of HAI-1 in tet-off MCF-7 cells suggests that HAI-1 moderately slows the proliferation of these cells, but did not affect other measures such as in vitro cellular motility and in vivo tumor growth, invasion and metastasis. Expression of HAI-1 in MDA MB-435 cells, however, profoundly inhibited both in vitro cell proliferation and in vivo tumor growth. Expression of the inhibitor did not appear to affect in vitro cell motility or in vivo tumor metastasis, although metastatic disease tended to lack HAI-1 expression, in contrast to primary tumor xenografts, suggesting that HAI-1 expression may have been turned off during the metastatic process.