-edited) The applicant proposes to begin a new collaborative effort between basic and clinical laboratories to use information derived from the Drosophila model system to identify human tumor suppressor genes (TSGs) in which either inherited or somatic genetic alterations contribute to breast cancer. The work addresses two of the priority areas listed in the Request for Applications: namely, Breast Cancer Etiology and Breast Cancer Susceptibility Genes Issues. Furthermore, it tests an innovative new technique for the identification of susceptibility genes. It is a pilot project that, if successful, will yield important new information on breast cancer and could serve as the basis for more comprehensive future research in the area of breast cancer. Twenty drosophila genes have been identified in which loss of function mutations lead to excess cell proliferation in the imaginal discs, which are undifferentiated epithelial sacs in the larva that develop into adult structures during metamorphosis. In some cases the mutations also cause loss of epithelial structure and the ability to differentiate. Six of these genes have been cloned and characterized at the molecular level, and they all show clear homology to mammalian genes. These mammalian homologs, therefore, are considered candidate tumor suppressor genes (TSGs) for tumors derived from epithelial tissues. Breast tumor samples being accumulated under the auspices of the Cancer Surveillance Program of Orange County (CSPOC), will be screened for alterations in expression of the mammalian homologs. Normal breast RNA will be probed to determine which of the homologs are expressed in this tissue, and only those genes giving positive results will be studied further. Tissue sections will be screened for altered or lost expression of the candidate TSG products using immunofluorescence localization by confocal microscopy. Any genes showing changed expression in this screen will be further tested for loss of heterozygosity of closely linked DNA markers, a phenomenon which would suggest that the candidate gene is behaving as a classical TSG. Long-range goals include examination of these genes for mutations that might contribute to the development of breast tumors. This investigation may lead to the development of new reagents for diagnosis and/or targets for novel approaches to breast cancer treatment.
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