Elevated activity of membrane receptor and soluble protein tyrosine kinases (PTKs), occurs in a significant portion of breast tumors, and is indicative of a poor prognosis. These enzymes play a critical role in the regulation of normal cell growth and differentiation; their overexpression may confer a growth advantage to breast cancer cells by increasing sensitivity to locally acting peptide growth factors. It is important to define the role of less well-characterized PTKs as novel components of known signaling pathways also overexpressed in a large proportion of human breast cancers. A novel non-receptor PTK (Brk) was cloned from a human metastatic breast tumor, and found to be overexpressed in human breast carcinomas and breast cancer cell lines, but not in normal tissue. Although clearly in a novel family of soluble PTKs, Brk most closely resembles the Src oncogene, containing one SH3- and one SH2-domain. Overexpression of Brk transformed human mammary epithelial cells. This protein is associated with the epidermal growth factor (EGF) receptor in human breast cancer cells. Preliminary data suggests that EGF and progestins synergistically regulate Brk. It is hypothesized that Brk confers a growth advantage to human breast cancer cells by acting as a progestin-regulated signaling component in the EGF pathway. The hormonal control of Brk regulation will be addressed by : 1) defining Brk activation by upstream signals, 2) identifying regulatory phosphorylation sites of Brk in response to these signals, and 3) defining signaling pathways downstream of Brk by classical strategies involving """"""""pull-down"""""""" co-immunoprecipitation assays. The goal of the proposed studies is to demonstrate a role for signal transduction by a novel PTK (Brk) in breast cancer by defining the regulation and function of Brk as influenced by ovarian steroid hormones and peptide growth factors relevant to breast cancer cell biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK058347-02
Application #
6381864
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Blondel, Olivier
Project Start
2000-09-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$148,500
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ostrander, Julie H; Daniel, Andrea R; Lange, Carol A (2010) Brk/PTK6 signaling in normal and cancer cell models. Curr Opin Pharmacol 10:662-9
Zhang, Ping; Ostrander, Julie Hanson; Faivre, Emily J et al. (2005) Regulated association of protein kinase B/Akt with breast tumor kinase. J Biol Chem 280:1982-91