Molecular Control of Growth, Differentiation and Death in Breast Cancer Cells

Lipkowitz, S.

Abstract

""""""""Our laboratory investigations are focused on identifying genes that regulate growth, differentiation, and programmed cell death of normal and malignant mammary epithelial cells in order to develop rational strategies for the treatment of breast cancer. We have several ongoing projects: (1) We have cloned cbl-b and cbl-3, two new mammalian proteins with homology to the c-cbl proto-oncogene. cbl proteins are novel signal transduction molecules downstream of receptor tyrosine kinases. Studies in the nematode C. elegans suggest that the cbl homologue is a suppressor of epidermal growth factor receptor (EGFR) signaling. Ongoing work is focused on elucidating the role that cbl proteins play in the growth stimulation mediated by the EGF family of receptor tyrosine kinases in mammary epithelial cells. We have demonstrated that cbl-b and cbl-3 associate with the EGF receptor and inhibit signaling and are now investigating the biochemical mechanisms of this inhibition. (2) We are investigating the expression and function of death receptors of the TNFR family (e.g. TNFR, Fas, Dr3, Dr4, and Dr5) in normal and malignant breast epithelial cells. Ongoing projects are focused on exploring the normal physiologic role of the death receptors in mammary epithelial cells, the relationship of malignant transformation and the death receptor pathways, and the modulation of these pathways in breast cancer cells in vitro and in vivo.""""""""

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Intramural Research (Z01)
• Project #: 1Z01SC007263-06
• Application #: 6123700
• Study Section: Special Emphasis Panel (M)
• Support Year: 6
• Fiscal Year: 1998

Institution

• Name: National Cancer Institute Division of Clinical Sciences
• Country: United States

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

Rahman, Lambratu; Voeller, Donna; Rahman, Monzur et al. (2004) Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer Cell 5:341-51

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