Research Summary

Tissue remodeling is a process associated with both physiological and pathological conditions such as embryogenesis, wound healing, tooth eruption, arthritis, osteoporosis and cancer. This process involves the removal of extracellular matrix (ECM) and cell migration, two processes where the matrix metalloproteinases (MMPs) play a pivotal role. Impaired regulation of MMP expression and activity has been suggested as the cause for conditions such as delayed wound healing, tumor progression and metastasis.

My recent research focuses on the matrix metalloproteinase (MMPs) and their role and regulation during breast cancer progression and metastasis.  Under normal conditions, MMP activities are under tight control at either the transcriptional, translational or activity level. The MMP activity is regulated either by conversion of latent enzyme or through the interactions with the natural tissue inhibitors of metalloproteinases (TIMPs).

One of the MMPs, MMP-7 (matrilysin), is frequently up-regulated in colon carcinomas. MMP-7 is regulated at the level of translation by a polyamine-dependent mechanism that is currently being studied in the lab.

Current markers predicting recurrence and poor survival for breast cancer patients are inadequate, resulting in some patients being treated too aggressively and others not aggressively enough. Breast cancers that express both the membrane-type-MMPs (MT-MMPs) and TIMPs are predominantly found in specimens from women with disease-free survival. The tissue expression of these proteins are currently being investigate for their usefulness as prognostic markers for ductal breast carcinoma patients.

Selected Publications

1. Wallon, U.M. and O'Brien, T.G. (2005). Polyamines modulate carcinogen-induced mutagenesis in vivo. Environ. Mol. Mutagen. 45: 62-69.
2. Overall, C.M., Wallon, U.M., Steffensen, B., and Abbey, R. (2000). Interaction between tissue inhibitors of metalloproteinase and human gelatinase A/72-kDa type IV collagenase. In Tissue inhibitors of matrix metalloproteinases in health and disease, eds. Edwards, D., Hawkes, S., and Kokha, R. pp 57-69.
3. Overall, C.M., King, A.E., Sam, D.K., Ong, A.D., Lau, T., Wallon, U.M., DeClerk, Y.A., and Altherstone, J. (1999). Identification of the tissue inhibitor of metallo-proteinases-2 (TIMP-2) binding site on the hemopexin carboxyl domain of human gelatinase A by site-directed mutagenesis. J. Biol. Chem. 274:4421-4429.
4. Wallon, U.M., and Overall, C.M. (1997). The COOH-terminal hemopexin-like domain of human gelatinase A (MMP-2) requires Ca2+ for fibronectin and heparin binding: binding properties of recombinant gelatinase A C-domain to extracellular matix and basement membranes. J. Biol. Chem. 272:7473-7481.
5. Steffensen, B., Wallon, U.M., and Overall, C.M. (1995). Extracellular matrix binding properties of recombinant fribronectin type II-like modules of human 72-kDa gelatinase/Type IV collagenase. J. Biol. Chem. 270:11555-11566.
6. Wallon, U.M., Shassetz, L.R., Cress, A.E., Bowden, G.T., and Gerner, E.W. (1994). Polyamine-dependent expression of the matrix metalloproteinase matrilysin in a human colon cancer-derived cell-line. Mol. Carcinog. 11:138-144.

Spring Colloquium 2004 Virtual Poster

Prognostic Markers in Breast Cancer