Opposing Roles of Nucleophosmin and the ARF Tumor Suppressor in Breast Cancer

摘要

The ARF tumor suppressor protein plays an important role in the tumor surveillance of human cancer. In the search for novel ARF binding proteins, we uncovered NPM. Despite the important role ARF plays in the regulation of tumorigenesis, alterations selectively affecting its ability to negate NPM function have not been studied. In our proposed study, we aimed to determine the impact of ARF-NPM interactions in the pathogenesis of breast cancer. To this end, we have found that overexpression of NPM in the absence of ARF is a powerful transforming event. NPM promotes tumorigenesis without affecting genomic stability, implying that the subsequent tumors should remain diploid, a hallmark of ARF-null breast cancers. Indeed, when we analyzed sixty breast carcinomas, NPM was highly overexpressed in 50% of cases. We have begun further analyses of how NPM promotes tumor formation and have discovered that it does so through ribosome dysregulation, opening up the door to new therapeutic targets in breast cancer: protein synthesis.