Research

Cancer genetics and eEpigenetic Mechanisms pursues basic and translational research to discover novel cancer genetic and epigenetic mechanisms, to translate mechanistic insights derived principally from mouse models and primary human cancer samples to human cancer, and to leverage the mechanistic insights to advance cancer diagnosis and treatment.

Cancer genetics and epigenetics are central to the research of Drs. Christopher Bradfield, Aussie Suzuki, Beth Weaver,  Wei Xu, and Jing Zhang. The scientific basis of these studies arises from the fact that cancer is a genetic disease encompassing both germline and somatic genetics. Current areas of research include:

• Mouse and rat models to study basic and translational aspects of colon cancer. These efforts include biomarker development as well as advanced imaging applications. A recent advance is an Apc-mutant rat model that enhances the modeling of familial human colon cancer.
• Mouse models to identify genes predisposing individuals to the risk of developing liver and pancreatic cancer. The liver work focuses on the interaction of genetics and hormonal exposure in the etiology of hepatic carcinoma.
• Rat models to study the etiology and prevention of breast cancer. These studies integrate genetic studies in the rat with studies of human DNA from epidemiology-linked breast cancer case-control studies. For example, studies on the Rat Mcs5a quantitative trait locus led to the identification of an orthologous human locus associated with breast cancer risk.
• Mouse models to study environmental xenobiotics.
• Epigenetic transcriptional control of breast cancer. This work specifically focuses on histone H3 methylation by CARM1 and activation of the estrogen receptor.
• Mouse models for hematopoietic cancers and the study of genetic changes that alter the balance in growth versus differentiation properties o fhematopoietic stem cells (HSCs) and their progeny lead to these cancers.
• State of the art microscopy methods and drug studies to define molecular signals and cellular machinery that determine accurate division of cellular chromosomes during mitosis and consequences of mistakes in these processes leading to aneuploidy and its effect on cancer.
• Defining the role of epigenetic dysregulation in cancer.

Tumor biology includes research groups working on aspects of cell biology, stem cells, transcriptional regulation and protein structure relevant to cell growth regulation, differentiation and cancer.

Tumor biology includes research groups working on aspects of cell biology, stem cells, transcriptional regulation and protein structure relevant to cell growth regulation, differentiation and cancer. McArdle faculty with research interests focused on these areas of tumor biology are: Drs. Christopher Bradfield, Dustin Deming, Yongna Xing, Wei Xu, and Jing Zhang. Current areas of research include:

• Roles of estrogen receptors, estrogen-related receptors and post-transcriptional mechanisms of estrogen receptor in breast cancer.
• Oncogenic pathways and modifiers of breast cancer cell behavior including TGFβ, the RNA binding protein CRD-BP, Ras, neu, and Wnt signaling.
• Structural biology of protein phosphatase 2A and other molecular targets in cancer cells.
• Roles of hematopoietic stem cells and Ras signaling in mouse models of leukemia.
• Effects of carcinogen exposure and the aryl hydrocarbon receptor.
• Development of chemoprotective molecules for alleviating side-effects of chemotherapy.
• Defining new approaches to targeting estrogen receptor in recurrent, metastatic breast cancer.
• Lipid metobolism/deposition in the skin and its role in cancer and meta “bolic homeostasis”.
• Studies of NFkappaB signaling in cancer and immunology.
• Use of 3-dimensional cultures to test patient’s tumor’s response to targeted therapy– a new pathway to precision medicine.

Human tumor viruses are causally associated with over 15% of all human cancers and are likely to contribute to additional cancers. Recent research in our program and elsewhere clearly demonstrates that, for many virus-associated cancers, viral gene functions are required both for tumor development and also for continued survival of malignant cells. Thus, inhibiting tumor virus infection, replication and maintenance, and/or selected viral oncogenic functions can prevent or cure many of these cancers.

Tumor virology is represented by Drs. Paul Ahlquist, Eric Johannsen, Robert Kalejta, Shannon Kenney, Paul Lambert, Dan Loeb, Nate Sherer, Megan Spurgeon, and Bill Sugden. The strong motivation for this program is that viruses are now known to cause at least 15%-20% of human tumors, and are widely suspected in additional cancers. In many or most of these cases, viral gene functions not only contribute to tumor development, but also are required for continuing survival of the final malignant tumor. Thus, interfering with virus infection or viral functions could prevent or cure many cancers. Current areas of research include:

Epstein-Barr Virus (EBV)

• Studies on the replication and partitioning of EBV DNAs between dividing cells, EBV control of cell proliferation, and the interaction of EBV viral and cellular microRNAs (miRNAs) with infection and oncogenesis.
• Studies on EBV latent infection and lytic reactivation, including the roles of viral DNA methylation and host proteins in these processes. Recent work showed that cellular Hsp90 is required for normal expression of EBNA2, an important EBV-transforming protein.
• Developing treatments for EBV-associated tumors based on reactivation of lytic EBV replication and/or inhibiting EBV functions required for viral maintenance, cell survival and proliferation

Kaposi’s Sarcoma-associated Herpes Virus (KSHV)

• Studies on viral DNA partitioning required to maintain the latent infections associated with tumorigenicity.

Human Cytomegalovirus (HCMV)

• Studies on latent and lytic herpesvirus replication. Recent work has shown that HCMV modulates cellular Rb function in part through a viral kinase that acts as a hyperactive ortholog of cellular cyclin-dependent kinases.

Human Papillomaviruses (HPVs)

• Studies on the pathways and mechanisms of HPV infection, maintenance, and oncogenesis.
• Specific roles of viral oncogenes, cell genes and hormones in HPV-associated oncogenesis in different tissues. Recent studies show that p53 loss synergizes with estrogen and papillomaviral oncogenes to induce cervical and breast cancers.
• Fundamental differences in cell cycle deregulation in human papillomavirus-positive and -negative head/neck and cervical cancers.

Hepatitis B virus (HBV)

• Studies on the molecular processes by which the virus maintains its genome and chronic infections that lead to progressive liver damage and hepatocellular carcinoma.

Hepatitis C virus (HCV)

• Studies on the molecular processes by which the virus maintains its genome and chronic infections that lead to progressive liver damage and hepatocellular carcinoma.