Summer 2003 - Research Project

Corey Kebert

Cory is interested in learning about Pathology and laboratory research, which he sees as being vital in the future of medicine. He is curious to learn more about MTHFR mutations, and expects to gain knowledge and confidence while working in our labs.

Title of Project

Role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) Mutations (C677T, A1298C, and G1793A) in Patients with Varying Degrees of Angiographically Demonstrated Coronary Artery Disease



Faculty Mentor

S. Terence Dunn, PhD

The project will identify the distribution of three MTHFR mutations, C677T/A1298C/G1793A, in a large (n=850) Oklahoman population of hospital admits for chest pain.   We hope to identify the association of MTHFR mutations with the degree of angiographically detected coronary artery disease (CAD) in these patients by applying statistical analysis of genotype results in the context of extensive pre-existing clinical history and previously acrued results of other biomarkers of cardiovascular disease.

Elevated levels of homocysteine are generally accepted as increasing one's risk for CAD and are purported to be associated with several mutations in the MTHFR gene.  We hypothesize that the examination of the most penetrant MTHFR gene mutations (C677T, A1298C, and G1793A) in a large population of patients, with or without angiographically diagnosed and/or other risk factors for CAD, will show minimal or no correlation with risk for CAD.

David A. Neumann, II

David is especially interested in the pathology of tumorigensis. Mr. Neumann will apply his knowledge of molecular biology to the project, and appreciates the opportunity to learn about breast cancer. His goal is the gain a comprehensive understanding of the relationship between estrogen, Her-2/neu and breast cancer.

Title of Project

Interactions between Hormonal and Receptor Tyrosine Kinase Pathways in Breast (Mammary Gland) Cancer

Faculty Mentor

Bolin Liu, MD, MS

In Dr. Ann Thor's laboratory, genetically at risk virgin transgenic mice (bearing the rat wt erbB-2 gene under control of MMTV promoter) were utilized to study the effects of hormonal factors on mammary carcinogenesis.  Upon administration of 17beta-estradiol (E2), tamoxifen, or placebo via a subcutaneous constant release pellet during mammary gland development, mice mammary tumor development, latency, tumor histology and grade, metastasis, and breast morphogenesis were studied.  They have discovered that breast cancer incidence and latency were significantly different in virgin mice treated with either E2 or tamoxifen as compared to placebo.  The timing and dose of E2 pellet placement also played important roles in mammary tumor latency and phenotype, including variation in histologic tumor grade, multifocality of cancer development and the number of pulmonary metastasis.  Mice fed a soy meal based chow (Purina 5001) developed mammary tumors with a longer latency, than comparable casein fed mice in the 0.5 mg E2 and placebo pellet treated groups.

The results from Dr. Thor's research program demonstrated that estrogenic promotion or blockade via either exogenous hormones or dietary sources, particularly during the late risk window/early reproductive period, significantly altered mammary morphogenesis and carcinogenesis in the wt erbB-2 transgenic mouse.  Whereas this transgenic mouse model serves as a useful approach to study signaling interactions between steroid hormones and erbB-2 in vivo, the cell lines derived from the mice tumors will be valuable for in vitroexperiments to investigate the mechanism(s) by which the estrogen/estrogen receptor (E2/ER) interacts with erbB2 signaling transduction.  Two important erbB2 downstream transduction pathways, PI-3 kinase/Akt pathway and MEK/MAP kinase pathway, will be our main focus.  Upon treatment with estrogen (E2) or genistein (a major component of soy), the cultured tumor cells will be collected and subjected to a series of biological assays.  In addition to examining the protein expression and phosphorylation with western blot, I will also study the protein-protein interaction with immunoprecipitation-western blot and protein kinase activity with the immunocomplex kinase assay.  Cell cycle progression changes will be detected by flow cytometry.  The results will further our understanding of the cross-talking between hormonal and receptor tyrosine kinase pathways in breast (mammary gland) cancer development.