The normal p53 gene product plays a key role in blocking cell division. Many human cancers, e.g., of the colon, breast, lung and brain, retain only a mutant allele of the gene and lose the other copy altogether. When wild type p53 is reintroduced into cancer cells, their rapid cell division stops completely. We now think that most cancer cells are under a strong selection pressure to circumvent the growth suppressing functions of the normal p53 protein one way or another. However, in breast cancer, only about 30% of the cases carry inactivating p53 mutations. My work has produced strong evidence that breast cancer can utilize an alternative pathway to eliminate p53 function: wild type p53 is inactivated on the level of the protein by excluding it from the cell nucleus, its site of action, and accumulating it in the cytoplasm. This is intriguing, since it might be important for the understanding of other cancers with a relatively low incidence of p53 mutations (ovarian, prostate, thyroid, certain lung cancers, etc.).
The specific aims of this proposal are to use biochemical and genetic techniques to determine the importance and elucidate the molecular mechanism of this pathway.
The specific aims i nvolve: a) enlarging the database of the original observation, b) establishing in vitro models to be used in experimental manipulations, c) testing if chemical modifications of the p53 protein and/or an abnormal 'anchor' protein exist to account for the exclusion, and d) gaining insight into p53 regulation of normal breast cells by examining a similar type of p53 exclusion that occurs during pregnancy and lactation. The design of future cancer therapies will use an approach that reintroduces essential elements that the normal cell uses to control cell division. Since p53 will be at the forefront of this effort, it is crucial that we understand the various mechanisms by which cancer cells inactivate this protein.
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