- Associate Professor
1567 Irving Hill Rd
Lawrence, KS 66045
- Protein Chemistry and Molecular Cell Biology
- Bioorganic & Bioanalytical Chemistry
Understanding the roles of lysyl oxidases in breast cancer metastasis and invasion
In 2013, it is estimated that 296,000 women in the U.S.A. will be diagnosed with breast cancer. Among those who are diagnosed before their cancer has started to spread, 99% will still be living 5 years after their diagnosis. However, for women who have progressed to distant-stage/metastatic breast cancer (i.e. cancer that has spread to other parts of the body), the 5-year survival rate plunges to ~24%; these women will account for the vast majority of the expected 40,000 breast cancer deaths in 2013. The dramatic decline in survival rate highlights the critical need to answer two pressing questions:
- What are the molecular mechanisms that drive the progression of breast cancer from a localized tumor (i.e non-invasive) to a raging horde of invasive cancer cells?
- How can progression of the metastatic potential/invasiveness of tumor cells be slowed, stopped, or even reversed?
In recent years, lysyl oxidase (LOX) and lysyl oxidase-like 2 (LOXL2) have been identified as contributors to increased breast cancer invasion/metastasis. These two proteins are Cu2+- and lysine tyrosylquinone cofactor-dependent amine oxidases. Traditionally, LOX has been known for its role in promoting the crosslinking of collagen and elastin, thereby facilitating construction of the extracellular matrix. This activity is essential to normal tissue development and wound healing. However, over-expression of LOX and LOXL2 is associated with increased invasiveness of breast cancer cells, and generally indicates a poor outlook for breast cancer patients.
How do LOX and LOXL2 contribute to cancer metastasis/invasion, and how could their actions be inhibited? We are currently applying a combination of techniques (e.g. bioorganic chemistry, biochemistry, bioanalytical chemistry, molecular cell biology, molecular imaging, and in vivo studies) to unveil the exciting and surprising answer(s) to these questions. Ultimately, we hope that these answers will guide the rational design of specific inhibitors (i.e. therapeutic drugs) that could be used to combat metastatic cancers.
Selected Publications —
Xu, L., Go, E. P., Finney, J., Moon, H., Lantz, M., Rebecchi, K.R., Desaire, H., and Mure, M. “Post-translational Modifications of Recombinant Human Lysyl Oxidase-like 2 (rhLOXL2) Secreted from Drosophila S2 Cells” J. Biol. Chem. 2013, 288, 5357-5363.
Rebecchi, K.R., Go, E. P., Xu, L., Woodin, C. L., Mure, M., and Desaire, H. “A General Protease Digestion Procedure for Optimal Protein Sequence Coverage and PTM Analysis of Recombinant Glycoproteins: Application to the Characterization of hLOXL2 Glycosylation” Anal. Chem. 2011, 83(22), 8484-8491
Chang, C. M., Klema, V. J., Johnson, B. J., Mure, M., Klinman, J. P., and Wilmot, C. M. "Kinetic and Structural Analysis of Substrate Specificity in Two Copper Amine Oxidases from Hansenula polymorpha". Biochemistry, 2010, 49, 2540-2550.
Reed, T., Lushington, G. H., Xia, Y., Hirakawa, H., Travis, D. M., Mure, M., Scott, E. E., and Limburg, J. "Crystal Structure of Histamine Dehydrogenase from Nocardioides simplex" J. Biol. Chem., 2010, 285(33), 25782-25791.
Mure, M. “Chapter 3. Cofactors: Copper and TPQ.” in “Copper Amine Oxidases Structures, Catalytic Mechanisms, and Role in Pathophysiology” edited by Floris, G. and Mondovi B. 2009 CRC Press, Boca Raton, FL.
Knowles, P., Kurtis, C., Murray, J., Saysell, C., Tambyrajah, W., Wilmot, C., McPherson, M., Phillips, S., Dooley, D., Brown, D., Rogers, M., and Mure, M. "Hydrazines and Amphetamine Binding to Amine Oxidase: Old Drugs with New Prospects" J. Neural. Transm., 2007, 114, 743-746.
Moore, R. H., Spies, M. A., Culpepper, M.B., Murakawa, T., Hirota, S. Okajima, T., Tanizawa, K., and Mure, M. "Trapping a Dopaquinone Intermediate in the TPQ Cofactor Biogenesis in a Copper-Containing Amine Oxidase from Arthrobacter globiformis" J. Am. Chem. Soc., 2007, 129, 11524-11534.
Mure, M., Kurtis, C. R., Brown, D. E., Rogers, M., Wilmot, C. M., Parsons, M., Phillips, S. E. V., McPherson, M. J., Knowles, P. F. and Dooley, D. M. “Active Site Rearrangement of the 2-Hydrazinopyridine Adduct in E.coli Amine Oxidase to an Azo Cu(II) Chelate form: A Key Role for Y369 in Controlling the Mobility of the TPQ-2HP Adduct" Biochemistry, 2005, 44, 1583-1594.
Mure, M., Brown, D. E., Saysell, C., Kurtis, C. R., Rogers, M., Wilmot, C. M., Phillips, S. E. V., McPherson, M. J., Knowles, P. F. and Dooley, D. M. "Role of the Interactions between the Active Site Base and the Substrate Schiff Base in Amine Oxidase Catalysis. Evidence from Structural and Spectroscopic Studies of the 2-Hydrazinopyridine Adduct of E.coli Amine Oxidase." Biochemistry, 2005, 44, 1568-1582.
Mure, M. "Tyrosine-derived Quinone Cofactors." Accounts. Chem. Res., 2003, 37, 131-139.
Mure, M., Wang, S. X. and Klinman, J. P. "Synthesis and Characterization of Model Compounds of the Lysyl Tyrosine Quinone (LTQ) Cofactor of Lysyl Oxidase." J. Am. Chem. Soc., 2003, 125, 6113-6125.
Kishishita, S., Okajima, T., Kim, M., Yamaguchi, H., Hirota, S., Suzuki, S., Kuroda, S., Tanizawa, K. and Mure, M. "Role of Copper Ion in Bacterial Copper Amine Oxidase: Spectroscopic and Crystallographic Studies of Metal-substituted Enzymes."J. Am. Chem. Soc., 2003, 125, 1041-1055.
Mure, M., Mills, S. A. and Klinman, J. P. "Catalytic Mechanism of the Topa Quinone containing Copper Amine Oxidases."Biochemistry, 2002, 41, 9269-9278.
Wang, S. X., Mure, M., Medzihradszky, K. F., Burlingame, A. L., Brown, D. E., Dooley, D. M., Smith, A. J., Kagan, H. M. and Klinman, J. P. "A Crosslinked Cofactor in Lysyl Oxidase - Redox Function for Amino Acid Side Chains." Science, 1996, 273, 1078-1084.
Awards & Honors —
NSF CAREER MCB-0747377 ”Mechanistic studies of tyrosine derived cofactors”