The EGF receptor and neu receptor are tyrosine kinases regulated by their respective peptide growth factor ligands. The EGF and neu receptors are involved in stimulating mitogenic signal transduction pathways which cause proliferation of mammary carcinoma cells. The objective is to identify compounds and gene therapy approaches to inhibit receptor-mediated stimulation of mammary carcinoma cell growth. Designing mutant inhibitory genes in combination with pharmacological inhibitors of EGF/neu receptor functions are predicted to synergistically arrest mammary carcinoma cell growth. The approach is to use dominant negative mutants of proteins required for EGF/neu receptor signaling. Expression of these growth inhibitory genes in mammary carcinoma cells will be accomplished using adenovirus expression. The adenoviruses will encode cDNAs that express fusion proteins having Src homology (SH) domains 2 and 3 within their sequence that will disrupt binding and activation of phospholipase C-gamma, P13 kinase and the adaptor protein Grb2 that is involved in Ras activation. Other adenovirus vectors will encode proline-rich SH3 domain binding sequences or a dominant negative mutant Raf. Expression of these mutant proteins will be used to define dominant sites in the EGF/neu receptor signal transduction pathways that when disrupted strongly inhibit mammary carcinoma cell growth. Tyrosine kinase inhibitors, EGF receptor and neu receptor antibodies, and other pharmacological agents that inhibit EGF and neu receptor signal transduction will be used in combination with the inhibitory gene products. The goal is to translate the findings to an effective strategy to inhibit the growth of breast cancer cells in women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK048845-04
Application #
2518401
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Sato, Sheryl M
Project Start
1994-09-30
Project End
1998-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Risérus, Ulf; Willett, Walter C; Hu, Frank B (2009) Dietary fats and prevention of type 2 diabetes. Prog Lipid Res 48:44-51
Erickson, Timothy; Scholpp, Steffen; Brand, Michael et al. (2007) Pbx proteins cooperate with Engrailed to pattern the midbrain-hindbrain and diencephalic-mesencephalic boundaries. Dev Biol 301:504-17
Schlesinger, Thomas K; Bonvin, Christelle; Jarpe, Matthew B et al. (2002) Apoptosis stimulated by the 91-kDa caspase cleavage MEKK1 fragment requires translocation to soluble cellular compartments. J Biol Chem 277:10283-91
Schwertfeger, K L; Richert, M M; Anderson, S M (2001) Mammary gland involution is delayed by activated Akt in transgenic mice. Mol Endocrinol 15:867-81
Yujiri, T; Ware, M; Widmann, C et al. (2000) MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation. Proc Natl Acad Sci U S A 97:7272-7
Sun, W; Vincent, S; Settleman, J et al. (2000) MEK kinase 2 binds and activates protein kinase C-related kinase 2. Bifurcation of kinase regulatory pathways at the level of an MAPK kinase kinase. J Biol Chem 275:24421-8
Gibson, S B; Oyer, R; Spalding, A C et al. (2000) Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Mol Cell Biol 20:205-12
Reyland, M E; Barzen, K A; Anderson, S M et al. (2000) Activation of PKC is sufficient to induce an apoptotic program in salivary gland acinar cells. Cell Death Differ 7:1200-9
Gibson, S; Tu, S; Oyer, R et al. (1999) Epidermal growth factor protects epithelial cells against Fas-induced apoptosis. Requirement for Akt activation. J Biol Chem 274:17612-8
Hunter, S; Burton, E A; Wu, S C et al. (1999) Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphatidylinositol 3-kinase. J Biol Chem 274:2097-106

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