) 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.
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