Abstract

Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. We are investigating the induction of apoptosis by activation of death receptors for the ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in breast and ovarian cancer cells. Previously, we have shown that many breast and ovarian cancer cell lines are resistant to the induction of apoptosis by TRAIL, the ligand for the death receptors DR4 and DR5. We have demonstrated that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, semi-synthetic retinoids (such as 4HPR), or molecularly targeted agents (such as anti-ErbB-2 antibodies). Our current work utilizes biochemical and genetic approaches to identify mechanisms that regulate the induction of death by TRAIL ligand in breast and ovarian cancer cells. Recently, we have shown that TRAIL selectively kills triple-negative breast cancer cells that have mesenchymal features. Ongoing work is investigating the molecular basis for this selectivity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC007263-16
Application #
7735380
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2008
Total Cost
$433,310
Indirect Cost

  Institution

Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

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
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
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