Maspin, a unique
serine proteinase inhibitor (
serpin), plays a key role in mammary gland development and is silenced during
breast cancer progression.
Maspin has been shown to inhibit
tumor cell motility and invasion in cell culture, as well as growth and
metastasis in animal models. In this study, we investigated the effect of
maspin on the regulation of
hypoxia-induced expression of
urokinase-type plasminogen activator (uPA) and its
receptor (uPAR), with respect to invasive potential in metastatic breast cells MDA-MB-231. We hypothesized that
maspin can neutralize or mitigate
hypoxia-induced expression of uPA/uPAR in metastatic
breast cancer cells, resulting in suppression of their invasive potential. To test our hypothesis, we employed the highly invasive MDA-MB-231
breast cancer cells that are devoid of
maspin, and transfected them with the
maspin gene, and then determined the effect of
hypoxia on uPA/uPAR expression. Normal mammary epithelial cells 1436N1 were used as a control. Our findings demonstrate that
maspin downregulated the basal and
hypoxia-induced uPA/uPAR expression and reduced the stimulatory effect of
hypoxia on the in vitro invasive ability of MDA-MB-231-cells. In addition,
maspin also inhibited the enzymatic activity of secreted and cell associated uPA in MDA-MB-231 cells. These results indicate that
maspin inhibits
hypoxia-induced invasion of metastatic
breast cancer cells by blocking the uPA system, thus illuminating an important molecular pathway for therapeutic consideration.