Colon cancer is the second leading cause of cancer death in the U.S., and in the obese population the risk of developing colon cancer is elevated by 2-fold, which is among the largest increases in risk seen for any obesity associated cancer. The goals of this project are to demonstrate that increased colon cancer risk is associated with obesity per se, and not with increased dietary fat intake, to elucidate the role of increased IGF1 signaling as a mediator of the obesity associated increased colon cancer risk, and to further identify key genes whose expression within the human colon is altered by obesity and by altered IGF1 signaling. This project is based on the unique development by our group of C57bl/6 derived chromosome substituted mouse strains that are either obesity sensitive or obesity resistant when placed on a high fat diet, and also on the unique finding by our group of mutational activation of IGF1 signaling in frank colon cancers due to mutational activation of PIK3CA, an early transducer of IGF1 signaling. Our specific studies will be: i) To compare the intestinal tumor promoting effects of high fat diet in mice that become obese on this diet (obesity sensitive) versus mice that do not develop obesity (obesity resistant), when these mice are engineered to carry the intestinal tumor inducing APC mutant Min allele. ii) To employ expression microarrays to identify those mouse genes whose expression in the intestine is regulated by obesity, that is genes whose expression is modulated by a high fat diet only in obesity sensitive, but not in obesity resistant mice. To further identify which of these obesity regulated genes demonstrates altered expression in a microarray comparison of colonic epithelium from obese versus non-obese humans. iii) To construct transgenic mice in which an activated mutant PIK3CA gene is specifically targeted for expression in the intestine. Further, by comparing tumor development in obese versus non-obese mice carrying this transgene, to determine whether the tumor promoting effect of activated IGF1/PIK3CA pathway signaling is epistatic with (in the same pathway with), or is independent of the tumor promoting effects of obesity. iv) To compare the activation of IGF1 signaling in normal human colon mucosa from obese versus non-obese individuals by using quantitative immunohisochemistry to compare in these tissues the levels of phosphorylation of key IGF1 activated signaling molecules: IGF1R, AKT and mTOR. Moreover, to identify those genes whose expression in the mouse intestine is altered by increased IGF1/PI3KCA signaling, and to further identify if this """"""""IGF1 signaling signature"""""""" of altered gene expression is evidenced on microarray comparison of gene expression in the colons of obese versus non-obese humans.
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