Known breast cancer risk factors do not completely explain the increase in breast cancer incidence inthe U.S. since 1940. It has been suggested that environmental chemicals, including polycyclic aromatichydrocarbons (PAH), have played a role in human breast cancer. PAH-induced tumorigenesis is initiatedthrough the AhR, an evolutionary conserved transcription factor activated by ubiquitous environmentalpollutants. In the original PO1, we proposed the novel hypothesis that the AhR plays an important role inmalignant epithelial cell growth in part through interaction with the Wnt/CK2 and NF-xB signaling pathways.Collaborative studies with Drs. Sonenshein and Seldin have strongly supported this hypothesis and haveprovided new evidence suggesting an important role for the AhR in tumor progression as well. Consequently,a new hypothesis is proposed: As mammary epithelial cells progress from normal to immortalized cells andthen to invasive tumors, AhR activity is modified through interactions with environmental chemicals, othertranscription factors, and cofactors to differentially regulate target gene transcription and to effect changes incell growth and invasiveness.
Three aims are proposed: 1) Assess AhR-mediated tumor invasion in vitro:AhR regulation of cell invasion in 3-dimensional cultures and the potential for the AhR to influenceinvasiveness through modulation of Slug will be evaluated. Collaborative studies will assess the role of AhRCK2interactions in tumor invasiveness. These mechanistic studies will provide the basis for complementarystudies evaluating tumor invasion in vivo. 2) Map differential cofactor recruitment by constitutively activeAhR: Studies will quantify binding of the AhR to regulatory elements within genes differentially regulated bythe AhR and will reveal the spectrum of coregulators recruited by constitutively active and chemical-activatedAhR in cells representing different levels of malignancy. Collaborative studies will evaluate AhR-NF-KBinteractions that may influence AhR activity. 3) Define the functional consequences of constitutively activeAhR in vivo: Stable cell lines in which AhR activity has been modulated (Aim 1), will be exploited in axenograft mammary tumor model to study the role of the AhR in mammary tumor cell growth in situ. Thecontribution of enforced AhR expression in mammary epithelial cells also will be evaluated with MMTV-AhRtransgenic mice. Evidence of AhR contributions to tumor growth and invasion provided by these studieswould link environmental exposures to tumor aggressiveness and would strongly encourage translationalstudies with selective AhR inhibitors. New information will be obtained on AhR function in normal ascompared with malignant cells, on differential control of gene transcription by the AhR, and on the molecularand functional outcomes of constitutively activated as compared with environmental chemical-activated AhR.The results will help place AhR function in the continuum of malignant transformation and will further expandon our central theme of biologically significant interactions between AhR, CK2 and NF-KB during mammarytumorigenesis.
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