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Mechanism of Environmental Carcinogen-Induced Mammary Tumorigenesis

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Annual rept. 30 Sep 1998-29 Sep 1999

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Environmental pollutants such as polycyclic aromatic hydrocarbons PAH are believed to contribute to the recent increase in breast cancer incidence and mortality. Yet, the molecular mechanism is poorly understood. In this study, we use a carcinogen-induced breast cancer animal model in which the female Sprague-Dawley S-D rats develop mammary tumors after a single intragastric dose of treatment of 7,1 2-dimethylbenzaanthracene DMBA, a member of the PAM family. Estrogen is indispensable for the DMBA-mediated mammary tumorigenesis. We hypothesize that DMBA and estrogen receptor ER cooperate in activation of protooncogene Mdm2 which is important for DMBA-rat mammary tumorigenesis. We have confirmed that MDM2 is indeed overproduced in DMBA-mammary tumors, likely via a post-transcriptional mechanisms. Analysis using the Rat cDNA Expression Array indicates an up-regulation of p450, as expected, as well as the down regulation of IGFl, IGF1R, c-Myc and JNK in the DMBA-treated mammary glands at an early stage of the DMBA treatment. We have also found a clear correlation between MDM2 expression and the status of the aromatic hydrocarbon receptor AhR and ER in a number of human breast cancer cells. MDM2 expression in MCF-7 cells is activated in a DMBA dose- and time-dependent manner. We show that at least two cellular proteins can specifically interact with an AhR site in MDM2 5 UTR. We conclude that overproduction of MDM2 may play a pathological role in carcinogen-induced mammary tumorigenesis and that MDM2 is upregulated by AhR and ER independent of p53 action.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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