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Chemoprevention of Colorectal Cancer: The Potential Role for and Function of Indole-3-Carbinol
Gregory D Kennedy*, Carol Diaz-Diaz*, Sean Ronnekleiv-Kelly*, Manabu Nukaya*, Bruce A Harms
University of Wisconsin, Madison, WI

Objectives: Exposure to polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (BZ), increases the risk for the development of colorectal cancer (CRC). We hypothesized that the receptor for BZ, the aryl hydrocarbon receptor (AHR), would function as an oncogene in the colon.
Methods: Wild-type C57BL/6J (Bl6, N=36) or Bl6 mice congenic for deletion of the AHR locus (AHR-/-, N=20) were maintained on chow or chow supplemented with Indole-3-carbinol (I3C) and exposed to a two-stage model of CRC. Tumor incidence, number and location were visually counted. Statistical analysis was performed using GraphPad Prism software (version 5, LaJolla, CA).
Results: We found colorectal tumors in 100% of AHR-/- and 68% of wild-type mice (P<0.05). Mean tumor number was also significantly increased in AHR-/- (6 v 3, P<0.05) while tumor distribution was similar in all mice. Figure 1 shows that 8% of mice treated with I3C supplemented diet had tumors present at the time of sacrifice compared to 83% of mice on regular chow diet (P<0.05).
Conclusions: Our findings are consistent with the conclusion that AHR is a tumor suppressor gene in the large intestine. In support of this, we found the AHR agonist I3C prevents the development of colon tumors in an AHR-dependent fashion. This work supports the application of I3C as a chemopreventive agent for CRC in humans.


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