Ph.D., University of Wisconsin-Madison, Oncology, 1989.
M.S., Oregon State University, Fisheries Science, 1984.
B.A., Case Western Reserve University, Biology, 1980.
Environmental and genetic control of cancer cell evolution
The goal of our research is to understand how environmental exposure to carcinogens interacting with the genetic susceptibility of the host leads to cancer. As a basic research laboratory, we study multistage carcinogenesis in the mouse in order to model the entire natural history of neoplastic development from the initiated cell to clonal evolution to a fully malignant tumor. This has the following benefits: the influence of the host genetic background (e.g., susceptibility and resistance loci or modifier genes) can be studied; the role of particular genes can be studied using transgenic and knockout mice; somatic genetic or epigenetic changes (e.g., mutations in oncogenes and tumor suppressor genes) driving clonal neoplastic evolution and their phenotypic consequences can be studied in detail; and finally the specific effects of different carcinogen treatments on tumor development can be studied. More recently we are using mouse models of cancer to improve methods for biomarker discovery and validation using proteomics, micro RNA and other approaches for the early detection of cancer or for monitoring tumor response to therapy.
As a hallmark of the cancerous cell is loss of genetic fidelity, we are focusing on mutations in genes which control the cell cycle and/or the faithful segregation of genetic material as likely rate limiting steps. The p53 tumor suppressor gene is one such gene. It is mutated in the majority of human cancers and plays a critical role in maintaining genetic fidelity. p53 is normally induced in response to DNA damage or oncogene signaling, resulting in cell cycle arrest, senescence or apoptosis which inhibits the propagation of cells which have potentially neoplastic mutations. This pathway may also be important in the success or failure of chemo- or radio-therapy for cancer. We are addressing the following questions regarding p53 function: (1) What regulates p53 during tumor development? Our results show that oncogene signaling through p19/Arf as opposed to DNA damage signaling through Atm, is the major pathway of p53 regulation during tumor evolution. We are now pursuing how loss of p19/Arf and p53 lead to more aggressive tumors and metastatic dissemination.
We have recently shown that DNA damage can induce apoptosis in the absence of p53, and this pathway is regulated by the DNA repair enzyme DNA-PK. We are pursuing the mechanism of this novel apoptotic pathways and if this pathway can be used to increase the sensitivity of tumors to radio- or chemo-therapy.
Expression of the CDK inhibitor p27/kip1 is an important prognostic marker in almost all the major types of human cancer. Following the discovery that p27 is haplo-insufficient for tumor suppression using mouse models, we are identifying mechanisms and pathways that regulate p27 in tumors and the mechanism by which p27 regulates tumor aggressiveness. In particular we are pursuing the role of p27 in tumor metastasis.
More recent efforts in the lab are directed toward using mouse models of cancer for biomarker discovery using a comprehensive systems biology approach. Another new avenue is the role of epigenetics in dietary or radiation induced cancer and transgenerational inheritance. A third area is based on two of our observations. One is synthetic lethality between the DNA damage response proteins Atm and DNA-PK and the second observation is that DNA-PK regulates a novel p53 independent cell death pathway. We are applying functional genomics with high throughput siRNA to identify mechanisms of these cell death pathways and plan to validate them as drug targets in preclinical cancer models.
American Association for Cancer Research
American Association for the Advancement of Science
International Mammalian Genome Society
Doxorubicin, DNA torsion, and chromatin dynamics.. Biochimica et biophysica acta. 1845(1):84-9.. 2014.
Systematic Screen Identifies miRNAs that Target RAD51 and RAD51D to Enhance Chemosensitivity.. Molecular cancer research : MCR.. 2013.
Doxorubicin Enhances Nucleosome Turnover around Promoters.. Current biology : CB. 23(9):782-7.. 2013.
Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer.. Epigenetics : official journal of the DNA Methylation Society. 8(12):1254-60.. 2013.
Functional genomics to identify unforeseen cancer drug targets.. Future oncology (London, England). 9(4):473-6.. 2013.
ARF suppresses hepatic vascular neoplasia in a carcinogen-exposed murine model.. The Journal of pathology. 227(3):298-305.. 2012.
MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency.. Molecular cancer research : MCR.. 2012.
Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos.. PloS one. 7(4):e34915.. 2012.
Lung cancer signatures in plasma based on proteome profiling of mouse tumor models.. Cancer cell. 20(3):289-99.. 2011.
A targeted proteomics-based pipeline for verification of biomarkers in plasma.. Nature biotechnology. 29(7):625-34.. 2011.
Tumor Microenvironment-Derived Proteins Dominate the Plasma Proteome Response during Breast Cancer Induction and Progression.. Cancer research. 71(15):5090-100.. 2011.
Proteome and transcriptome profiles of a Her2/Neu-driven mouse model of breast cancer.. Proteomics. Clinical applications. 5(3-4):179-88.. 2011.
Plasma proteome profiles associated with inflammation, angiogenesis, and cancer.. PloS one. 6(5):e19721.. 2011.
Mapping tissue-specific expression of extracellular proteins using systematic glycoproteomic analysis of different mouse tissues.. Journal of proteome research. 9(11):5837-47.. 2010.
Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer.. Oncogene. 28(41):3652-62.. 2009.
Endocrine dysfunction in p27Kip1 deficient mice and susceptibility to Wnt-1 driven breast cancer.. Carcinogenesis. 30(6):1058-63.. 2009.
DNA-PK suppresses a p53-independent apoptotic response to DNA damage.. EMBO reports. 10(1):87-93.. 2009.
N-linked glycoproteomic analysis of formalin-fixed and paraffin-embedded tissues.. Journal of proteome research. 8(4):1657-62.. 2009.
p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis.. Oncogene. 27(22):3145-55.. 2008.
Tumor suppression by p53 in the absence of Atm.. Molecular cancer research : MCR. 6(7):1185-92.. 2008.
p27kip1 deficiency impairs G2/M arrest in response to DNA damage, leading to an increase in genetic instability.. Molecular and cellular biology. 28(1):258-68.. 2008.
A mouse model repository for cancer biomarker discovery.. Journal of proteome research. 7(8):3613-8.. 2008.
Plasma proteome profiling of a mouse model of breast cancer identifies a set of up-regulated proteins in common with human breast cancer cells.. Journal of proteome research. 7(4):1481-9.. 2008.