The protective role of the AhR Repressor in breast cancer development

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Summary/Abstract The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds. Due to the widespread occurrence in our environment and the high toxic potential, these contaminants are of concern to promote malignancies including breast cancer. More recently it has been found that the AhR may also act as a critical receptor protein in tumor promotion independent from exogenous ligands, which is based on immune tolerance and increased survival in cancer cells. Consequently, the AhR has emerged as an attractive target for new drugs in cancer therapy. Furthermore, the AhR's action is restricted by a specific repressor protein, the AhR Repressor (AhRR). The AhRR is a ligand-independent, transcriptionally inactive AhR-like protein and is thought to repress AhR signaling. While AhRR effectively blocks AhR, the role of AhRR as a tumor suppressor gene is only poorly understood. We established a transgenic mouse (AhRR Tg mice) that overexpresses AhRR and discovered that these mice were protected from dioxin-induced lethality associated with a reduction in inflammatory responses. Inflammatory processes have emerged as a major factor promoting cancer development, which has been shown also in the case of TCDD-induced liver inflammation and its tumor promoting effects. Significant gaps exist in our understanding how the AhRR regulates AhR signaling and its adverse outcome pathways leading to deregulated inflammatory responses and tumor promotion. Preliminary data show that overexpression of AhRR suppresses tumor growth of E0771 breast cancer cells in mice after subcutaneous challenge. AhRR Tg mice were also partially protected against bacterial lipopolysaccharide- (LPS) promoted growth of breast cancer cells indicating its potential to suppress inflammatory-dependent promotion of breast cancer. How the AhRR inhibits AhR signaling and expression of inflammatory markers is of critical importance in order to understand AhRR's protective role in breast tumorigenesis. Our central hypothesis is that AhRR will function, in vivo, to oppose AhR's role in mammary tumor formation. While AhRR has been studied in cells and is very promising, it is not yet known whether it will function as hoped in a pre-clinical mouse model. In this regard, we have at hand a novel resource, the B6 AhRR transgenic mouse crossed into the B6 PyMT strain, a suitable mouse model to study breast cancer. Based on our results and the current literature, our overarching interests include: (a) Does the AhRR suppress mammary tumor growth and/or progression in vivo and repress inflammatory responses? (b) How does the AhRR abolish resistance to apoptosis and what anti-apoptotic genes are involved in breast cancer cells, particularly if the AhR is activated by toxic environmental ligands? This study design will help to understand the pathway and potential marker genes of AhR-mediated mammary tumorigenesis and AhRR's anti-inflammatory role and function as a tumor suppressor gene.