Abstract

Over the past year, we have investigated whether transforming mutants of the Epidermal Growth Factor Receptor (EGFR), such as EGFRvIII, are regulated by Cbl proteins. We have shown that Cbl proteins can ubiquitinate and down regulate the oncogenic form of the EGFR, EGFRvIII. Our data indicated that the amplification and overexpression of the constitutively active EGFRvIII accounts for its transforming ability and that EGFRvIII does not escape normal negative regulatory mechanisms. We have continued to study the induction of apoptosis by TRAIL in breast cancer cells. We have shown that inhibitors of the EGFR can enhance TRAIL-mediated apoptosis in breast cancer cells which express EGFR. Interestingly, it appears that the subset of breast cancer cells which do not express estrogen receptor or ErbB-2 are most affected by EGFR inhibition. These estrogen receptor and ErbB-2 negative tumors have a poor prognosis and can only be treated with chemotherapy. Our data raise the possibility of using molecularly targeted therapy (e.g., the combination of EGFR inhibitors and TRAIL) for the treatment of these tumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC007263-14
Application #
7331410
Study Section
(LCMB)
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2006
Total Cost
Indirect Cost

  Institution

Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Sadarangani, Anil; Kato, Sumie; Espinoza, Natalia et al. (2007) TRAIL mediates apoptosis in cancerous but not normal primary cultured cells of the human reproductive tract. Apoptosis 12:73-85
Peschard, Pascal; Kozlov, Guennadi; Lin, Tong et al. (2007) Structural basis for ubiquitin-mediated dimerization and activation of the ubiquitin protein ligase Cbl-b. Mol Cell 27:474-85
Lipkowitz, Stanley; Dennis, Phillip A (2007) PPARgamma agonists follow an unknown TRAIL in lung cancer. Cancer Biol Ther 6:107-9
Ryan, Philip E; Davies, Gareth C; Nau, Marion M et al. (2006) Regulating the regulator: negative regulation of Cbl ubiquitin ligases. Trends Biochem Sci 31:79-88
Choong, Nicholas W; Dietrich, Sascha; Seiwert, Tanguy Y et al. (2006) Gefitinib response of erlotinib-refractory lung cancer involving meninges--role of EGFR mutation. Nat Clin Pract Oncol 3:50-7; quiz 1 p following 57
Davies, G C; Ryan, P E; Rahman, L et al. (2006) EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins. Oncogene 25:6497-509
Calzone, Kathleen A; Prindiville, Sheila A; Jourkiv, Oxana et al. (2005) Randomized comparison of group versus individual genetic education and counseling for familial breast and/or ovarian cancer. J Clin Oncol 23:3455-64
Zeng, Shan; Xu, Zhiheng; Lipkowitz, Stan et al. (2005) Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl). Blood 105:226-32
Peschard, Pascal; Ishiyama, Noboru; Lin, Tong et al. (2004) A conserved DpYR motif in the juxtamembrane domain of the Met receptor family forms an atypical c-Cbl/Cbl-b tyrosine kinase binding domain binding site required for suppression of oncogenic activation. J Biol Chem 279:29565-71
Davies, Gareth C; Ettenberg, Seth A; Coats, Ashley O et al. (2004) Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b. Oncogene 23:7104-15

Showing the most recent 10 out of 25 publications