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Apo2L/TRAIL as a regulator of cell death in transformed cells
Summary
We have identified that PTHrP expression by breast cancers modulates tumour response to TRAIL. We aim to identify the mechanism by which PTHrP confers enhanced TRAIL sensitivity.
Description
Disturbances in mechanisms that direct abnormal cells to undergo cell death frequently and critically contribute to tumourigenesis, yielding a logical target for potential therapeutic intervention.
There is currently heightened interest in the extrinsic apoptosis pathway, with several pro-apoptotic receptor agonists (PARAs) in development. One of these PARAs include the recombinant ligand Apo2L/TRAIL.
Gene array studies comparing cancer cells that respond to Apo2L/TRAIL compared to those that do not respond have identified several genes that may be involved in determining cell fate.
This project examines the role of these genes with a particular emphasis on overcoming Apo2L/TRAIL resistance. Notably, PTHrP expression by breast cancers alters their response to TRAIL as well as several target genes within the TRAIL pathway.
Funding
National Breast Cancer Foundation
Selected Publications
Zopf, S., Neureiter, D., Bouralexis, S., Abt, T., Glaser, K.B., Okamoto, K., Ganslmayer, M., Hahn, E.G. and Ocker, M. (2007). Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo. International Journal of Oncology. 31, 1391-1402.
Thai, le M., Labrinidis, A., Hay, S., Liapis, V., Bouralexis, S., Welldon, K., Coventry, B.J., Findlay, D.M. and Evdokiou, A. (2006). Apo2l/Tumor necrosis factor-related apoptosis-inducing ligand prevents breast cancer-induced bone destruction in a mouse model. Cancer Research 66, 5363- 5370.
Fisher, J.L., Thomas-Mudge, R.J., Elliott, J., Hards, D.K., Sims, N.A., Slavin, J., Martin, T.J. and Gillespie, M.T. (2006). Osteoprotegerin over-expression by breast cancer cells enhances orthotopic and osseous tumor growth, and contrasts with that delivered therapeutically. Cancer Research. 66, 3620-3628. Reported in The BreastCancer.Net News.
Bouralexis, S., Findlay, D.M. and Evdokiou, A. (2005). Death to the bad guys: targeting cancer via Apo2L/TRAIL. Apoptosis 10, 35-51.
Price, J.T., Quinn, J.M.W., Sims, N.A., Moore, J., Waldeck, K., Docherty, S.E., Myers, D., Nakamura, A., Waltham, M.C., Gillespie, M.T. and Thompson, E.W. (2005). The HSP90 inhibitor, 17-AAG, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Cancer Research. 65, 4929-4938.
Jans, D.A., Thomas, R.J. and Gillespie, M.T. (2003). Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. In "Vitamins and Hormones", Edited by Gerald Litwack. Elsevier Science, pp. 345-384.
Guise, T.A., Yin, J.J., Thomas, R.J., Dallas, M., Cui, Y. and Gillespie, M.T. (2002). Parathyroid hormone-related protein (PTHrP)-(1-139) isoform is efficiently secreted in vitro and enhances breast cancer metastasis to bone in vivo. Bone. 30, 670-676.
Conlan, L.A., Martin, T.J. and Gillespie, M.T. (2002). The C-terminus of parathyroid hormone-related protein (PTHrP) interacts with b-arrestin 1B. FEBS Letters. 527, 71-75.
Thomas, R.J., Guise, T.A., Yin, J.J., Elliott, J., Horwood, N.J., Martin, T.J., and Gillespie, M.T. (1999). Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 140, 4451-4458.