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RFA CA-03-001: Cooperative Grants for Nutritional Modulation of Genetic Pathways Leading to Cancer

Albert Einstein Cancer Center
Montefiore Medical Center
Department of Medical Oncology
Bronx, NY

Leonard H. Augenlicht, PhDPrincipal Investigator:
Leonard H. Augenlicht, PhD

Project Summary

"Molecular Nutrient Interaction in Intestinal Cancer"

Technologies, including microarray analysis, novel transcriptional imaging methods, and laser capture microdissection, will be used to study how a Western style diet that mimics the major risk factors for colon cancer interacts with genetic factors to increase the likelihood of tumors forming in the intestinal tract. These risk factors include a diet high in fat and phosphate, low in calcium, vitamin D, choline, methionine, folate and fiber. In addition, human subjects will be fed diets in which components such as calcium and vitamin D are altered, and biopsies will be taken at various points to study the interaction of diet, intestinal cell changes, biomarkers and profiles of gene expression, and to make comparisons to mouse models used in earlier phases of the project and existing gene expression data bases.

Project 1 Goals

  • To complete development and characterization of a mouse with a point mutation in the ATP binding site of the Msh2 gene which is pathogenomic for mutations found in some HNPCC kindreds.
  • To conduct histopathological and microarray analysis of mice that represent a matrix of interactions between genetic and nutritional factors that elevate risk for development of intestinal cancer. The genetic factors consist of Apc and Muc2 inactivation and Msh2 mutation, and the dietary factors are a western style diet that is high in fat, low in calcium and vitamin D, folate, choline, methionine and fiber, and diets with each of these nutritional risk factors adjusted to lower risk.

Project 2 Goals

  • To determine if the short-chain fatty acid butyrate induced a transcriptional pause in the cyclin D1 gene as it does in c-myc (Wilson et al, Cancer Res. 62, 6006, 2002).
  • To determine the complexes which regulate cell cycling during normal homeostasis of the intestinal mucosa, and how these are perturbed by genetic and dietary factors that increase risk for tumor formation.

Project 3 Goal

  • To enter human subjects into dietary modulation studies in the Rockefeller GCRC and to test how nutritional components could shift profiles of gene expression.

Research is supported by four cores.

Core A

The administrative core, the New York Colon Cancer Study Group (NYCCSG), meets every six weeks and includes:

  • Albert Einstein Cancer Center, Montefiore Medical Center
  • Strang Cancer Prevention Center, Rockefeller University
  • University of Nebraska
  • North Shore
  • NY Medical Center, Valhala

Core B

The histopathology core

Core C

The molecular biology core

Core D

Analysis of extensive gene expression data bases

References

Maridason JM, Nicholas C, L'Italien KE, et al. Gene expression profiling of intestinal epithelial cell maturation along the crypt-villus axis. Gastroenterology 2005;128(4):1081-8.

Song Z, Tong C, Liang J, et al. JNK1 is required for sulindac-mediated inhibition of cell proliferation and induction of apoptosis in vitro and in vivo. Eur J Pharmacol 2007;560(2-3):95-100.

Stempelj M, Kedinger M, Augenlicht L, Klampfer L. Essential role of the JAK/STAT1 signaling pathway in the expression of inducible nitric-oxide synthase in intestinal epithelial cells and its regulation by butyrate. J Biol Chem 2007;282(13):9797-804.

Klampfer L, Huang J, Kaler P, et al. STAT1-independent inhibition of cyclooxygenase-2 expression by IFNgamma; a common pathway of IFNgamma-mediated gene repression but not gene activation. Oncogene 2007;26(14):2071-81.

Yang W, Bancroft L, Liang J, et al. p27kip1 in intestinal tumorigenesis and chemoprevention in the mouse. Cancer Res 2005;65(20):9363-8.

Yang W, Velcich A, Lozonschi I, et al. Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2-/- mice. Am J Pathol 2005;166(4):1239-46.

Yang W, Bancroft L, Augenlicht LH. Methylation in the p21WAF1/cip1 promoter of Apc+/-, p21+/- mice and lack of response to sulindac. Oncogene 2005;24(12):2104-9.

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