Inhibition of Breast Cancer-Induced Angiogenesis by a Diverged Homeobox Gene
Annual rept. 14 Apr 2004-13 Apr 2005
UNIVERSITY OF MEDICINE AND DENTISTRY OFNEW JERSEY PISCATAWAY
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Homeobox genes represent a class of transcription factors important in embryogenesis, organogenesis, cell growth and differentiation, and cell migration. However, there is little known about their role in regulating endothelial cell EC phenotype in response to proangiogenic factors secreted by breast cancer, although at least two homeobox genes have been implicated in inducing the angiogenic phenotype in ECs. We are therefore testing the homeobox gene Gax regulates breast cancer-induced angiogenesis through its ability to regulate the expression of downstream target genes in ECs. Using an in vitro tube formation assay, we have found that Gax expression inhibits in vitro angiogenesis. Moreover, by real time quantitative reverse transcriptase PCR, we have found that Gax expression is downregulated by proangiogenic factors and, by cDNA microarray analysis, that Gax downregulates pro-angiogenic adhesion molecules in ECs and upregulates the cyclin-dependent kinase inhibitor p191NK4D. In addition, we have observed that Gax expression downregulates NF-kB-dependent gene expression in ECs and inhibits the binding of NF-kB to its consensus sequence. These observations will allow us to study the mechanism of Gax-mediated activation or repression of their expression to be studied and will form the basis for future studies that will examine in more detail the mechanism by which Gax activates downstream target genes in both ECs and breast cancer cells themselves and the detailed signaling pathways involved in this activation, specifically NF-KB, Wnt, and TGF-beta signaling. Given the profound effect Gax has on endothelial cell activation, it is likely that these studies will identity new molecular targets for the antiangiogenic therapy of breast cancer. Ultimately, these same techniques will be applied to other homeobox genes implicated in regulating EC phenotype during breast cancer-induced angiogenesis.
- Anatomy and Physiology
- Medicine and Medical Research