Every year approximately 200,000 new cases of breast cancer are diagnosed, and 40,000 women are expected to die from this disease in the U.S. alone. Our lab's long-term goal is to identify novel therapeutic targets for treatment of breast cancer. We are trying to understand alterations in cellular signaling pathways between normal and cancer cells and exploit these differences for possible therapeutic gain.
Our lab has two major areas of interest:
1. We are trying to understand how cancer cells survive in the absence of cell adhesion. Normal epithelial cells readily undergo cell death in the absence of matrix signals (referred to as anoikis). Cancer cells, and oncogenes such as tyrosine kinase family of receptors, provide survival signals that allow anoikis resistance and enable cancer cell to survive in inappropriate environments and spread. Our lab has found a critical interplay between specific adhesion receptors (integrins) with the EGF receptor family of tyrosine kinase receptors in regulating anoikis. In addition, in collaboration with Dr. Gregg Johannes (Dept. of Pathology), we are examining how low oxygen levels (hypoxia) regulate matrix-mediated survival pathways in standard and three-dimmensional epithelial culture assays.
2. Recently, our lab has become interested in understanding how metabolic reprogramming in cancer cells alters signaling regulating oncogenic pathways. Tumor cells take up 10 times more glucose than normal cells and switch to glycolysis to meet energy needs. In collaboration with Dr. Keith Vosseller (Department of Biochemistry & Molecular Biology), we have found that a nutrient-sensing pathway that regulates sugar-based protein modification, called O-GlcNAcation, is highly elevated in a number of cancers. Reducing O-GlcNAcation in cancer cells inhibits growth and invasion, and thus may provide a novel way to treat cancers. We are currently investigating how O-GlcNAcation regulates oncogenic signaling pathways.
Selected Publications
1. Whelan, K. A., Caldwell, S. A., Shahriari, K., Jackson, S. R., Jones, L., Johannes, G. and Reginato, M. J. (2010) Hypoxia suppression of Bim and Bmf blocks anoikis and luminal clearing during mammary morphogenesis (Mol. Biol. Cell., under review).
2. Caldwell, S. A., Jackson, S. R., Shahriari, K. S., Lynch, T., Sethi, G., Walker, S., Vosseller, K., and Reginato, M. J. (2010) Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis via targeting of the oncogenic transcription factor FoxM1. Oncogene May 13: 29, 2831-42.
3. Haenssen, K. K., Caldwell, S. A., Shahriari, K., Jackson, R., Whelan, K., Klein-Szanto, A., and Reginato, M. J. (2010) ErbB2 requires integrin
alpha5 for anoikis resistance via c-Src regulation of receptor activity in human mammary epithelial cells. J. of Cell Science April 15: 123, 1373-82.
4. Sodunke, T. R., Turner, K. K., Caldwell, S. A., McBride, K. W., Reginato, M. J. and Noh, N. (2007) Micropatterns of matrigel for three-dimensional epithelial cultures. Biomaterials 28, 4006-16.
5. Reginato, M.J., and Muthuswamy, S.K. (2006) Illuminating the center: mechanisms regulating lumen formation and maintenance in mammary morphogenesis. J Mammary Gland Biology & Neoplasia 11, 205-11.
6. Reginato, M. J., Mills, K. R., Becker, E.B., Lynch, D.K., Bonni, A., Muthuswamy S., and Brugge, J. S. (2005) Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes. Mol. Cell. Biol. 25, 4591-4601.
7. Mills. K. R., Reginato, M. J., Debnath, J., Queenan, B., and Brugge, J. S. (2004) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc. Natl. Acad. Sci. USA, 101, 3438-3443.
8. Reginato, M. J., Mills, K. R., Paulus, J. K., Lynch, D. K., Sgroi, D.C., Debnath J., Muthuswamy S., and Brugge, J. S. (2003) Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nature Cell Biology 5, 733-740.
9. Debnath, J., Mills, K. R., Collins, N., Reginato, M. J., Muthuswamy S., and Brugge, J. S. (2002) The role of apoptosis in creating and maintaining luminal space within normal and oncogene expressing mammary acini. Cell 111, 29-40.
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