The Signaling Pathways of Metallothionein-Mediated Chemotaxis in Breast Cancer

Metallothionein (MT) is a small, thiol rich protein released into the extracellular environment in response to stress. Elevated expression of MT has been linked to many inflammatory diseases including inflammatory bowel diseases, diabetes, and cancer. In breast cancer, high expression of MT has been associated with poor patient prognosis. Previous studies have shown that MT acts as a chemoattractant in lymphocytes, and that UC1MT, a monoclonal anti-MT antibody, can block this chemotactic response. In addition, it has been shown that both Cholera toxin and Pertussis toxin, which are known antagonists of G-protein coupled receptors, can inhibit MT-mediated chemotaxis. Here, I investigate the signaling pathways of MT-mediated chemotaxis using small molecule inhibitors in cellular models of inflammation and breast cancer. I also examine the chemotactic potential of MT in mammary tumor cell lines and the ability of UC1MT to block this chemotactic response. Experiments revealed that MT is chemotactic in mammary tumor cell lines. I have found that, like in lymphocytes, MT interacts with receptor CXCR4 in breast cancer models to initiate the chemotactic response. Studies conducted using MT peptides revealed that MT’s N-terminus is likely involved in the binding of this protein to its receptor. MT-mediated chemotaxis in both immune cells and breast cancer cell models can be blocked using CK-666 and U73122, but not with PD98059, which suggests that the Arp2/3 complex and phospholipase C (PLC) are involved in MT’s chemotactic signaling pathways, but that mitogen activated kinase kinase (MEK) is not. Finally, I found that UC1MT can block MT-mediated chemotaxis in mammary tumor cell lines. This suggests that UC1MT may be a useful therapeutic to inhibit breast cancer metastasis