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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAQfV5-xLlpw3kxtvQ4VjUdtLbOMXTLLzcIv2KILNHN2Q#_4 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAQfV5-xLlpw3kxtvQ4VjUdtLbOMXTLLzcIv2KILNHN2Q#_3 http://www.w3.org/ns/prov#value STATs are important regulators of breast development and carcinogenesis. Constitutively elevated STAT DNA-binding activity is seen in primary breast tumor specimens from patients with advanced disease compared to adjacent nontumor tissues Constitutively active STAT3 mediates oncogenic transformation in immortalized fi- broblasts and induces tumor formation in nude mice, suggesting a pivotal role of STAT3 in transformation (48) Berclaz et al. found a very strong correlation between nuclear STAT3 andEGFRexpression in breast cancers cells. ProstaglandinHsynthetases (composed of Cox- 1 and Cox-2 isoenzymes) convert arachidonic acid into prostaglandins that are further modified to produce important signal molecules Induced Cox-2 expression is seen in almost all tumor sites. It was shown over a decade ago that both PGE1 and PGE2 enhance mitogenesis in mammary epithelial cells stimulated with EGF (165,166). In Hs578T breast cancer cells, Cox-2 expression is related to digestion of basement membrane, resulting in cellular invasiveness (167). Cox-2 expression is seen in the majority of HER2-overexpressing breast cancers, and in a small fraction of HER2-negative breast cancers as well (164) Posttranslational farnesylation is required for Ras to function in the inner membrane surface, a process catalyzed by farnesyl transferase. Substrates for this enzyme include all four Ras proteins as well as other non-Ras proteins (e.g., RhoB) that have the amino acid CAAX motif where X represents methionine or serine A direct role of Raf in the development of human cancers is well documented in literature (161). In MCF-7 cells, Raf-1 and A-Raf are upregulated after treatment with (-) estradiol, but not in ER-negative cells. Overexpression of constitutively active Raf-1 causes cell cycle progression and results in an increased proliferative response to (-) estradiol (273). Raf-1 protein is overexpressed in the cytosol fraction of human breast cancer tissues but not in normal mammary gland tissue ( Geldanamycin, herbimycin A, 17-allylaminogeldanamycin (17-AAG), radicicol, KF25706, and KF58333 represent a class of compounds that bind to heat-shock protein-90 (Hsp90) (Table II). They destabilize Hsp90-associating proteins including Raf- 1, ErbB2, Akt, p53, v-Src, Bcr-Abl, HIF-1a, ER, PR, and glucocorticoid receptors (277). Hence, geldanamycin and its analogs are not specific for any one target. Geldanamycin causes destabilization of Raf- 1 and loss of Raf-1-Ras association, the Raf-MEKMAPK signaling pathway (278,279). Geldanamycin increases the recruitment of chaperone-interacting protein (CHIP), which is known to efficiently ubiquitinate and down-regulate ErbB2 in COS7 cells (280). KF58333, an oxime derivative of radicicol, is a potent growth inhibitor of high- and low-Her2 expressing breast cell lines (212). 17-AAG, a geldanamycin analog, has less toxicity than its predecessor and is able to downregulate Akt expression, inhibit PI3K and Akt activity, suppress cyclin D expression, and ultimately inhibit growth of HER2-overexpressing breast cancer It has been shown that Akt has antiapoptosis effect by phosphorylating Bad and other death proteins (285-287). 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