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Roles for the Aryl Hydrocarbon Receptor in Tumor Suppression Public Deposited

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  • The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor of the basic helix-loop-helix PER ARNT SIM (bHLH PAS) family and regulates a diverse set of genes. The AhR is best known for directing the transcription of drug-metabolizing enzymes, particularly upon activation by ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs). However, the AhR also regulates gene programs upstream of organismal development, cellular differentiation, cell proliferation, and programmed cell death. The roles of AhR in mediating cellular fate coupled with its ability to respond to both exogenous and endogenous chemical signals make its behavior in the context of cancer particularly interesting. Recently, we reported that low expression of AhR correlates with poor prognosis for breast cancer patients, adding to the accumulating evidence that AhR is able to mediate tumor suppressive effects in tissues. The central hypothesis of this research is that the aryl hydrocarbon receptor functions as a tumor suppressor, and that the tumor suppressive activities of AhR can be therapeutically activated with selective AhR ligands.To test our hypothesis, we developed AhR-knockout mice lacking the tumor suppressor protein p53, mimicking the most common mutation event in the development of human cancers. The absence of AhR increased the tumor burden, tumor spectrum and reduced survival in p53-deficient mice, supporting a tumor modifier role for the AhR. Furthermore, the double-knockout of AhR and p53 resulted in reduced embryonic survival and neonatal fitness. These findings suggest important roles for the AhR in tumor suppression and development, and have significant clinical implications. To test the hypothesis that AhR is a molecular target for anti-cancer therapeutics, we screened chemical libraries for small molecules capable of both activating the AhR and inhibiting the growth of cancer cells. Of interest were the compounds that caused growth arrest or apoptosis in triple-negative breast cancer (TNBC) cells, as patients with TNBC have an extremely bleak prognosis characterized by poor responses to currently available therapeutics and a rapid rate of relapse. A short list of compounds that induced AhR-dependent anti-cancer effects was investigated to determine their mechanisms of action. One compound activated AhR-dependent transcription of cyclin-dependent kinase inhibitor 1B (CDKN1B p27Kip1), a cell cycle inhibitor and a tumor suppressor. As transcriptional regulation of p27Kip1 is a poorly understood phenomenon with implications for cancer treatment, we performed promoter analyses to determine regions critical to regulation of p27Kip1, and found evidence of transcriptional activation of p27Kip1 by the AhR. Given the potential for drug development, we then investigated the structural analogs of the p27Kip1-inducing compound for activation of AhR and subsequent transcriptional induction of p27Kip1, and restriction of TNBC cell growth. We selected ten analogs from a list of 517 based upon docking scores obtained from an in silico ligand screen using a model of the AhR ligand binding domain optimized for the binding of agonists. All ten were capable of activating the AhR, and eight showed efficacy in reducing TNBC cell viability. Further characterization revealed that several of these compounds also induced the transcription of p27Kip1 in an AhR-dependent manner. These findings suggest that AhR can be selectively activated by small molecules to induce specific anti-cancer genes.Collectively, this research establishes a role of the AhR in tumor suppression and provides evidence in support of the AhR as a therapeutic target in cancer. AhR modifies the phenotype of tumors driven by loss of the major tumor suppressor p53, and is thus a tumor modifier, if not a tumor suppressor. A novel AhR ligand that induces the transcription of p27Kip1 has been identified, and its efficacy against triple-negative breast cancer cell lines has been established. Overall, these studies support therapeutic targeting of the AhR for the treatment of cancers with defective p53 signaling. In addition, selective AhR ligands that induce the expression of p27Kip1 have the potential to treat cancers that respond poorly to currently available therapeutics.
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  • description.provenance : Rejected by Julie Kurtz(, reason: Hi Jessica,Rejecting because the page numbers start with the Table of Contents, so Chapter 1 starts on page 7. Pretext pages do not have page numbers and Chapter 1 should start on page 1 and renumber to the end of your dissertation.Also on the approval page there should be two signature lines that read - Co-Major Professor, representing Comparative Health Sciences. The third signature line should be changed to read - Dean of the College of Veterinary Medicine.Everything else looks good. Once revised, log back into ScholarsArchive and go to the upload page. Replace the attached file with the revised PDF and resubmit.Thanks,Julie on 2017-06-20T17:11:39Z (GMT)
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  • 2017-11-08 to 2019-07-12



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