Over expression of the receptor tyrosine kinase ERBB2 is important in breast cancer development. Inhibitors of ERBB2 signaling (e.g. Herceptin) are presently used to treat ERBB2 positive breast cancer. Unfortunately, response to Herceptin is poor; only 30% of patients that over express ERBB2 respond to Herceptin therapy. I postulate that this is due, in part, to tumor genetic variability, and that genes that cooperate with ERRB2 to drive breast cancer are variably mutated between patients. By identifying and characterizing these genes, it will be possible to improve clinical management of ERBB2 positive breast cancer by developing predictive markers of response to Herceptin therapy, and by developing drugs to target these genes that can be combined with Herceptin treatment. Through my genomic analyses of breast cancer, I have identified a genomic locus that is frequently deleted in ERBB2 positive human and mouse breast tumors, and hypothesize that this locus encodes a tumor suppressor gene (or genes) that act in concert with ERBB2 to drive tumor progression. I propose to identify and functionally characterize these genes through two specific aims. 1) I will precisely define the minimal regions of deletion in human and mouse breast tumors and cell lines and identify candidate genes using in silico strategies. Expression of candidates will be quantitatively and spatially assessed in breast tumors and cell lines; recurrently down regulated genes will be functionally interrogated in aim 2. Preliminary studies have identified SFN (14-3-3() as a high-ranking candidate. 2) SFN (and other candidates) will be tested in breast epithelial cells and tumor cell lines for its ability to abrogate ErbB2 mediated cellular transformation. SFN expression will be altered by cDNA, BAC, and siRNA transfections and effects on proliferation, apoptosis, and motility determined. Guided by these results, molecular and biochemical mechanisms of SFN mediated transformation inhibition will be determined by assessment of expression levels, subcellular localization, interactions with, and phosphorylation status of Erbb2 itself, key mediators of downstream Erbb2 signaling, and regulators of cell cycle progression, apoptosis, and motility. Finally, effects on in vivo tumorigenic potential will be assessed by evaluating tumor growth in immunedeficient mice. ? ?
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