Given the importance of environmental factors in colorectal cancer (CRC), it is widely held that the incidence of this disease can be significantly reduced through dietary alterations, supplementation or therapeutic administration of chemoprotective agents, or by preventing exposure to initiating or tumor promoting chemical exposures. The list of currently popular chemoprotective agents includes naturally occurring dietary compounds such as indole-3- carbinol, chrysin and curcumin, as well as therapeutic agents like Sulindac and Omeprazole. Interestingly, many proposed chemopreventative agents are known agonists of the aryl hydrocarbon receptor (AHR). We hypothesize that the AHR plays an important, yet complex, role in how environmental factors influence CRC in human populations. There are a number of data gaps that must be addressed before recommendations for increasing exposure to AHR agonists can be recommended with confidence. First, we must understand how AHR activation and AHR deletion in experimental animals lead to both increases and decreases in cancers at various sites. Second, we must understand whether AHR activation is an important step in the mode of action of known chemopreventative agents. If receptor agonism is mechanistically linked to chemoprevention, how do we modulate doses so that too much action does not mimic the procarcinogenic effects of dioxins? If it is not mechanistically related to chemoprevention, can we modify structures of the chemopreventative agents to minimize this off target AHR effect? We propose that the bifunctional role of the AHR in CRC can be explained using recombinant mouse models. We hypothesize that the pro- and anti-carcinogenic activity of the AHR depends upon the cell type in which the receptor is expressed and activated, as well as the degree to which the receptor is activated in that cell type. In addition, we propose that the activity of many chemopreventatives act, in part, by their ability to activate the AHR in specific cellular compartments and that this can be proven using recombinant models systems for CRC. To test these ideas, we offer the following specific aims:
Aim 1. Use cell specific deletion to determine tissue autonomy of AHR signaling and susceptibility to CRC.
Aim 2. Use models of conditional activation of AHR to determine tissue autonomy of AHR signaling and susceptibility to CRC.
Aim 3. Clarify the underlying mechanism of AHR-mediated tumor suppression using recombinant alleles of Arnt and Ahrr.
Chemicals that activate the aryl hydrocarbon receptor (AHR) are currently being used as chemopreventives of a number of cancers. This is problematic as AHR activation in experimental animals can both increase and decrease risk for cancers at various sites. Therefore, the goals of this proposal can be broadly defined as to better understand whether AHR activation is an important step in the mode of action of known chemopreventive agents. Second, to determine how to modulate doses of AHR agonists such too much action does not mimic the cancer causing side effects. Finally, to better understand the signaling events mediated by AHR agonists that are required for chemoprevention in an attempt to identify new agents that bypass the potential negative effects of AHR activation.