) The results of our studies with Keratinocyte Growth Factor (KGF) and the existing literature indicate that KGF has a rapid and profound influence on breast cancer cell motility. Based on these results, it appears that KGF, secreted from breast stromal tissue, may act as an early signal in tumor cell proliferation and the initiation of metastasis. If this hypothesis is correct, therapeutic inhibition of genes and/or proteins regulated by KGF, should impede the progression of ER-positive breast cancer cells to a metastatic phenotype and make the tumor more manageable by surgery, endocrine therapy or other cytotoxic agents. The central hypothesis, derived from the literature and our previous studies, is that KGF-regulated gene products induce cell scattering motility of human breast cancer cells, which may be an early event in the metastatic progression of primary tumor cells. Using cDNA expression arrays, we have identified a specific group of """"""""Candidate Target Genes"""""""", that are up or down regulated by KGF, which may be directly associated with KGF effects on breast cancer cells. The hypothesis to be tested in this proposal is that specific genes, regulated by KGF, are involved in mediating the motility of breast cancer cells. Selective inhibition of individual candidate genes, using antisense oligonucleotides, will be used to demonstrate the involvement of each gene product in KGF induced motility of breast cancer cells in culture and in mouse xenographs in vivo. The results of this study should lead to the identification of important new therapeutic targets and biomarkers involved in breast cancer cell progression and metastatic development. This should result in the development of new therapeutic agents that may be very specific and highly effective inhibitors of breast cancer progression and metastatic spread and/or provide critical new biomarkers for cancer staging and treatment design.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA089740-02
Application #
6514887
Study Section
Special Emphasis Panel (ZCA1-SRRB-7 (O1))
Program Officer
Wang, Wendy
Project Start
2001-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$72,750
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Zang, Xiao-Ping; Lerner, Megan; Brackett, Daniel et al. (2009) Influence of KGF on the progression of pancreatic cancer. Anticancer Res 29:3417-20
Zang, Xiao-Ping; Pento, J Thomas (2008) SiRNA inhibition of ER-alpha expression reduces KGF-induced proliferation of breast cancer cells. Anticancer Res 28:2733-5
Zang, Xiao-Ping; Pento, J Thomas; Tari, Ana M (2008) Wilms'tumor 1 protein and focal adhesion kinase mediate keratinocyte growth factor signaling in breast cancer cells. Anticancer Res 28:133-7
Hackett, John; Xiao, Zili; Zang, Xiao-Ping et al. (2007) Development of keratinocyte growth factor receptor tyrosine kinase inhibitors for the treatment of cancer. Anticancer Res 27:3801-6
Zang, Xiao-Ping; Bullen, Elizabeth C; Manjeshwar, Sharmila et al. (2006) Enhanced motility of KGF-transfected breast cancer cells. Anticancer Res 26:961-6
Zang, Xiao-Ping; Siwak, Doris R; Nguyen, Thi X et al. (2004) KGF-induced motility of breast cancer cells is dependent on Grb2 and Erk1,2. Clin Exp Metastasis 21:437-43
Peron, Karine; Jones, Tara N; Gauthier, Sebastien A et al. (2003) Targeting of a novel fusion protein containing methioninase to the urokinase receptor to inhibit breast cancer cell migration and proliferation. Cancer Chemother Pharmacol 52:270-6
Buller, C J; Zang, X-P; Howard, E W et al. (2003) Measurement of beta-galactosidase tissue levels in a tumor cell xenograft model. Methods Find Exp Clin Pharmacol 25:713-6
Zang, Xiao-Ping; Lerner, Megan R; Dunn, S Terence et al. (2003) Antisense KGFR oligonucleotide inhibition of KGF-induced motility in breast cancer cells. Anticancer Res 23:4913-9
Nguyen, Thao-Nguyen; Zang, Xiao-Ping; Pento, J Thomas (2002) Keratinocyte growth factor stimulates the migration and proliferation of breast cancer cells in a culture wounding model. Pharmacol Res 46:179-83

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