Breast cancer is a multi-faceted disease that affects a significant number of women (as many as 1 in 8) worldwide. The development of breast tumors is influenced by many factors including genetics, age, and endogenous (ie hormones) as well as exogenous environmental factors. We are interested in determining whether environmental factors interplay with the expression of previously identified cancer susceptibility genes including BRCA1, IGFI, and hTERT to influence the etiology of breast epithelial cell transformation. In studies investigating the function of the breast and ovarian susceptibility gene, BRCA1,we have found that BRCA1 acts as a transcriptional co-activator through a specific DNA binding site. We have identified several candidate proteins for complexing with BRCA1 on this site including the p53 and smad 4 tumor suppressor genes as well as the USF1/2 transcription factors. Further investigation has revealed that a protein produced from an alternate splicing event may account for most of BRCA1 action in normal cells and may attenuate the action of the full-length form of the protein. In addition, we have examined the activation of senescence/suppressor genes during growth inhibition of normal mammary epithelial cells including the identification of potential novel tumor suppressor genes that map to a """"""""hotspot"""""""" locus on chromosome 1. Finally, we have explored the interaction of signaling pathways affected by estrogen and insulin like growth factor treatment. We have identified a strong role for IGF I in production of angiogenic tumor progression factors in mammary epithelial cells.
