RNA-Binding Proteins as Novel Oncoproteins and Tumor Suppressors in Breast Cancer

摘要

Posttranscriptional control of gene expression is particularly important for oncoproteins and cell cycle proteins because their sustained synthesis favors cell growth rather than differentiation, a hallmark of the neoplastic phenotype. Control is exerted via the opposing actions of the RNA- binding proteins AUF1 and HuR. AUF1 triggers degradation of mRNA subsets while HuR promotes mRNA stabilization. Phase I of this work is to examine the effects of AUF1 and HuR expression levels on global gene expression in human breast carcinoma cells. Phase II is to assess roles of AUF1 and HuR in cellular proliferation and tumorigenesis in vivo. During this funding period, we discovered that AUF1 knockdown accelerates breast cancer cell proliferation and may convert cells to a highly metastatic state. Moreover, AUF1 knockdown elevates expression of the c-myc proto-oncogene, consistent with accelerated proliferation. mRNP immunoprecipitation and RT-PCR revealed that AUF1 binds c- myc mRNA in cells. Our results reveal a new paradigm for tumor metastasis and invasion in breast cancer.