Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in women in the United States. Breast cancer progression is accompanied by increased expression of extracellular proteases that are capable of degrading the extracellular matrix as well as cleaving and activating downstream targets including growth factors. These proteolytic processes are critically involved in modifying the tissue microenvironment of the breast, which is necessary for cancer cell invasion and eventual dissemination of cancer cells to other organs. We are studying two members of the type-II transmembrane serine protease (TTSP) family, matriptase and TMPRSS13, and their role in breast cancer.
Mice with reduced levels of matriptase, display a significant delay in oncogene-induced mammary tumor formation and blunted tumor growth. The abated tumor growth is associated with a profound decrease in cancer cell proliferation. The proliferation impairment in matriptase deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signaling pathway in response to fibroblast-secreted pro-HGF/SF. Inhibition of matriptase catalytic activity using a selective small-molecule inhibitor completely abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF/SF, which functionally leads to attenuated proliferation in breast carcinoma cells.
Similarly, results from prospective cohorts show that targeted deletion of TMPRSS13 results in attenuated onset of detectable mammary tumors, reduced total tumor burden, and decreased lung metastasis incidence. We are performing mechanistic studies to identify TMPRSS13 substrates that are relevant for its role in breast cancer progression. Overall, these studies are important to our understanding of the proteolytic mechanisms involved in breast cancer progression, and to identify potential therapeutic targets.