Post-transcriptional genetic deregulation in breast cancer

The control of mRNA translation and stability are highly regulated processes which are circumvented in cellular transformation. Translational control is an important target for upregulation as a component of malignant transformation of cells. Our research in this area is directed toward understanding how cellular protein synthesis is controlled and altered by the lack of oxygen (hypoxia) which often limits tumor growth, and how it is upregulated as a component of tumor invasiveness and metastasis in breast cancer. Our prior research on viral-host cell interactions at the level of translational control has provided insights into the deregulation of translation during cellular transformation and tumor progression. Ongoing studies are directed to understanding the pathways which control protein synthesis during breast cancer development and progression, during stresses that promote tumor progression such as hypoxia, and during angiogenesis that promotes new blood vessel growth into tumors. Other ongoing studies utilize breast tumor biopsies from clinical trials and model systems to determine alterations at the post-transcriptional level and in gene expression profiles (gene arrays) of different breast cancers that are associated with invasiveness and malignancy, and the response of tumors to different treatment strategies.

Pathogenesis and carcinogenesis by human hepatitis B virus (HBV)

HBV is a para-retrovirus that infects the liver and is strongly associated in humans with development of liver disease and liver cancer, a major form of cancer worldwide. The HBx protein is a regulatory protein that is involved in HBV infection, pathogenesis and possibly carcinogenesis. We previously established that HBx activates signal transduction pathways which are critical for HBV replication. We have also shown that the inflammatory cytokine TNF plays a role in inhibiting HBV replication and possibly in its clearance by disrupting the integrity of viral particles in infected cells. Ongoing studies are directed toward understanding the mechanism by which HBx functions in HBV replication in model animal and cell systems, and the molecular mechanisms by which inflammatory cytokines impair HBV replication.

Regulation of selective degradation of cytokine and proto-oncogene mRNAs and diseases associated with deregulation.

Many of the most powerful biological regulators of cell growth and proliferation are encoded by unstable mRNAs which are targeted for rapid degradation by the cell. The loss of rapid degradation of these mRNAs can result in a variety of inflammatory cytokine diseases and septic shock, as well as oncogenic transformation of the cell. Targeted degradation of short-lived cytokine and proto-oncogene mRNAs is controlled in a regulated manner by an AU-rich element (ARE) located in the 3' noncoding region, and by several proteins that bind this sequence. We have shown that activation of the ARE for mRNA decay involves cotranslation of the mRNA by ribosomes, involves the ubiquitin-proteasome pathway and is promoted by a related group of binding proteins known as AUF1. We are studying the mechanism for cotranslational degradation of short-lived mRNAs, the complex of proteins that act on the AU-rich element to control degradation and the diseases caused by knockout of these proteins in mouse model systems.