Tumorigenesis is a multi-step process the results in uncontrolled proliferation, invasion, and ultimately metastasis of tumor cells. This process frequently involves overexpression of signaling molecules otherwise involved in normal cellular proliferation and differentiation. Overexpression of the human epidermal growth factor receptor family (HER1/EGFR, HER2/neu, HER3, HER4) occurs in approximately 67 percent of human breast cancers. Overexpression of the non-receptor tyrosine kinase, c-Src, is found in close to 100 percent of breast tumors, and thus frequently accompanies EGFR overexpression. Since c-Src has been shown to potentiate EGF dependent DNA-synthesis in normal cells, co-overexpression of c-Src and EGFR in breast tumors suggests that c-Src may potentiate the role of HER family members in tumorigenesis. Human breast tumor cell lines which overexpress the EGFR and c-Src are characteristic of later stage tumors and poor prognosis. Identification of the downstream signaling molecules that are activated by overexpression of these two tyrosine kinases would provide targets for therapeutic intervention. The signal transducers and activators of transcription (STATs) are proteins that transmit a signal from a cytokine or growth factor receptor at the membrane of the cell to the nucleus where gene transcription is regulated. STATs are normally involved in the cellular process of proliferation, differentiation and apoptosis. Our preliminary evidence demonstrates that STAT proteins are activated in cells which overexpress the EGFR and c-Src in a manner dependent on EGFR kinase activity and c-Src mediated phosphorylation of the EGFR. Our hypothesis is that STAT proteins are one means by which a synergistic signal activated by EGFR and c-Src overexpression is transmitted to increase cell proliferation, transformation, and tumorigenesis. The following Specific Aims address this hypothesis: 1) Investigate the molecular mechanism of STAT5 activation in two tumorigenesis model systems; 2) Determine the role of STAT5 in transmitting the signal which leads to tumor function. The ultimate goal is that these studies will lead to the identification of novel therapeutic methods and/or reagents for treating breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085462-04
Application #
6697037
Study Section
Pathology B Study Section (PTHB)
Program Officer
Perry, Mary Ellen
Project Start
2001-02-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2006-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$162,800
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Weaver, Amanda M; Silva, Corinne M (2007) S731 in the transactivation domain modulates STAT5b activity. Biochem Biophys Res Commun 362:1026-30
Weaver, Amanda M; Silva, Corinne M (2007) Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6. Breast Cancer Res 9:R79
Weaver, Amanda M; Silva, Corinne M (2006) Modulation of signal transducer and activator of transcription 5b activity in breast cancer cells by mutation of tyrosines within the transactivation domain. Mol Endocrinol 20:2392-405
Boerner, Julie L; Biscardi, Jacqueline S; Silva, Corinne M et al. (2005) Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis. Mol Carcinog 44:262-73
Boerner, Julie L; Gibson, Matthew A; Fox, Emily M et al. (2005) Estrogen negatively regulates epidermal growth factor (EGF)-mediated signal transducer and activator of transcription 5 signaling in human EGF family receptor-overexpressing breast cancer cells. Mol Endocrinol 19:2660-70
Silva, Corinne M (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23:8017-23
Kloth, Michael T; Catling, Andrew D; Silva, Corinne M (2002) Novel activation of STAT5b in response to epidermal growth factor. J Biol Chem 277:8693-701