title: Id1 Deficiency Protects against Tumor Formation in Apc(Min/+) Mice but Not in a Mouse Model of Colitis-Associated Colon Cancer.
abstract: Different mechanisms contribute to the development of sporadic, hereditary and colitis-associated colorectal cancer. Inhibitor of DNA binding/differentiation (Id) proteins act as dominant-negative antagonists of basic helix-loop-helix transcription factors. Id1 is a promising target for cancer therapy, but little is known about its role in the development of colon cancer. We used immunohistochemistry to demonstrate that Id1 is overexpressed in human colorectal adenomas and carcinomas, whether sporadic or syndromic. Furthermore, elevated Id1 levels were found in dysplasia and colon cancer arising in patients with inflammatory bowel disease. Because levels of PGE2 are also elevated in both colitis and colorectal neoplasia, we determined whether PGE2 could induce Id1. PGE2 via EP4 stimulated protein kinase A activity resulting in enhanced pCREB-mediated Id1 transcription in human colonocytes. To determine the role of Id1 in carcinogenesis, two mouse models were used. Consistent with the findings in humans, Id1 was overexpressed in tumors arising in both Apc(Min) (/+) mice, a model of familial adenomatous polyposis, and in experimental colitis-associated colorectal neoplasia. Id1 deficiency led to significant decrease in the number of intestinal tumors in Apc(Min) (/+) mice and prolonged survival. In contrast, Id1 deficiency did not affect the number or size of tumors in the model of colitis-associated colorectal neoplasia, likely due to exacerbation of colitis associated with Id1 loss. Collectively, these results suggest that Id1 plays a role in gastrointestinal carcinogenesis. Our findings also highlight the need for different strategies to reduce the risk of colitis-associated colorectal cancer compared with sporadic or hereditary colorectal cancer.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Rhonda K
authors.initials: RK
authors.lastname: Yantiss
authors.affiliation: Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York.
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Chin
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. ajdannen@med.cornell.edu benezrar@mskcc.org.
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York. ajdannen@med.cornell.edu benezrar@mskcc.org.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D017491:Genes, APC / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology*; D051798:Inhibitor of Differentiation Protein 1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1