Alcohol is the dietary factor that has most consistently been associated with breast cancer risk, which is relative to estrogen receptor (ER). Studies have indicated that alcohol is more strongly related to ER+ than to ER- breast cancer. Cancer cells have a consistent cytological feature of nucleolar hypertrophy, where rRNAs are synthesized by RNA polymerase (Pol) 1 and III. Pathologists have been using enlarged nucleoli as a strong diagnostic indicator of cell transformation and neoplasia. This indicates that transformation in situ is tightly linked to the deregulation of RNA Pol I- and III gene transcription, because the size of the nucleolus reflects the levels of rRNA synthesis. However, the molecular mechanism of alcohol-associated breast cancer remains to be addressed. This study is designed to determine the mechanism of alcohol-induced RNA Pol III transcription in development of breast cancer. Our overall objective is to investigate what genes play a role in alcoholassociated breast cancer. Our hypothesis is that alcohol induces stress, stress activates MAP kinases, particularly c-Jun N-terminal kinases and increases RNA Pol Ill-dependent transcription, all leading to breast cancer. RNA Pol III is responsible for the synthesis of a variety of untranslated RNAs, such as tRNAs and 5S rRNAs. As these RNAs are major determinants of the biosynthetic capacity of cells, an alcohol-induced increase in RNA Pol III transcription may be fundamental to the development of breast cancer. Since deregulation of RNA Pol Ill-dependent genes would serve to enhance the translational capacity of cells, which is required to promote cellular growth, proliferation, transformation and tumor development, this suggests the RNA Pol III induction may be an early contributing event in the development of breast cancer. We will use a cell culture model, normal and tumor breast cell lines, to determine whether alcohol induces RNA Pol III transcription and to gain insights into the mechanism by which alcohol induces these genes. We will determine alcohol-induced changes in the RNA Pol III transcription components. We will identify specific signal transduction pathways mediating the alcohol-induced deregulation of these genes. We will further detect whether estrogen receptor involves in alcohol-induced RNA Pol III transcription. Elucidating these key molecular events triggered by alcohol will provide new insights into the pathogenesis of alcohol-associated breast cancer. Identification ofthe specific pathways in alcohol-induced RNA Pol III transcription will provide an opportunity to develop new drugs that could block alcohol-induced RNA Pol III transcription in order to therapy breast cancer patients. This study provides a completely new direction to understand the role of deregulation of RNA Pol III transcription in alcohol-associated breast cancer.
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