Jim Vaughn Lab
The goal of my laboratory is both to understand how normal breast epithelial cells develop into cancer cells and to identify methods that block or reverse the transformation. Loss of the BRCA1 tumor suppressor gene appears to be responsible for about 50% of familial breast cancer. The consequences of the loss of BRCA1 can serve as a model for the etiology of certain breast cancers. My work has suggested that the BRCA1 gene is utilized during cell proliferation at the start of the S phase of the cell cycle. Researchers have proposed that at that time, BRCA1 may induce gene expression or enhance DNA repair. By utilizing cell line knockouts for BRCA1 and cDNA expression vectors that restore BRCA1 function, we are investigating how BRCA1 expression affects gene transcription and repair. A second project in my laboratory concerns the development of antisense oligomer dendrimers used to down regulate expression of the oncogene erbB2. The erbB2 gene is over-expressed in about 30% of sporadic breast cancer and has been shown to be required for maintenance of the cancer phenotype. My work has shown that certain small chemically modified DNA oligomers complimentary to sequences of the erbB2 transcript efficiently induce destruction of the erbB2 message and cause down-regulation of the erbB2 protein. However, these oligomers cannot enter cells efficiently for therapeutic efficacy. In order to develop better antisense therapeutics, my collaborator Marvin Caruthers (whose expertise is in synthetic organic chemistry of nucleic acids) and I have proposed to investigate the biological applications of a group of novel antisense oligomer carrier macromolecules termed dendrimers. Dendrimers are loosely defined as three or more highly branched polymer chains originating from a central core. In creating macromolecu-lar dendrimers, subunits or synthons are constructed to form bonds with other synthons in a growing redundant array. The dendrimer concentrates antisense oligomers and can also serve as a platform for ligands and/or membrane-disrupting molecules such as fusogenic peptides. One particularly interesting dendrimer, which we have invented, uses a three-branched DNA molecule that has complementary ends which can self-assemble into macromolecules.