Mechanism of Environmental Carcinogen-Induced Mammary Tumorigenesis
Abstract
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,l2-dimethylbenz(a)anthracene (DMBA), a member of the PAH family. Estrogen is indispensable for the DMBA-mediated mammary tumorigenesis. We hypothesize that DMBA-mediated rat mammary tumorigenesis involves in the activation of protooncogene Mdm2 which in turn negatively regulates the tumor suppressor protein p53. We have confirmed that MDM2 is indeed overproduced in DMBA-mammary tumors by Western blot analysis and immunohistochemical staining. 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. Moreover, we have evidence that IGF-1 protects DNA damage-induced cell death by upregulation of p21 and MDM2. We conclude that overproduction of MDM2 may play a pathological role in carcinogen-induced mammary tumorigenesis, that MDM2 is upregulated by AhR and ER independent of p53 action.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2001
- Accession Number
- ADB282826
Entities
People
- Zhi-xiong J. Xiao
Organizations
- Boston Medical Center