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The Role of AhR in Breast Cancer Development

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Annual summary rept. 1 Jul 2003-30 Jun 2004

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It has long been suggested that ubiquitous environmental chemicals, such as PAH, contribute to human breast cancer. Most of the biologic activity of PAH and related dioxins is mediated by the AhR. We tested if constitutively active AhR in a human breast cancer cell line regulates c-myc, an important breast cancer gene which contains six AhR binding sites AhREs in its promoter. Our results indicate that 1 there is a significant baseline level of wildtype c-myc promoter driven reporter activity in these tumor cells which was not affected by inclusion of TCDD, a strong AhR agonist, 2 the baseline reporter activity was not affected by deletion of the NF-kB site, 3 while mutation of single AhRE sites had no effect on baseline reporter activity, mutation of all six sites resulted in a five fold increase in reporter activity a similar increase in reporter activity was seen when the wildtype reporter construct was co-transfected with an AhR repressor plasmid, 4 c-myc-specific real time PCR indicated that AhR repressor transfection increased background levels of endogenous c-myc mRNA. These results suggest that the AhR represses c-myc transcription and that AhR up-regulation in tumor cells may represent a failed growth feedback mechanism.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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