Department Affiliation: Primary: Oncology; Secondary: Urology; Pharmacology and Molecular Sciences; Medicine; Pathology; Radiation Oncology and Molecular Radiation Sciences
Joint: Environmental Health Sciences
Degree: M.D., Ph.D., Johns Hopkins University
Rank: Professor
Telephone Number: 410-614-1661
Fax Number: 410-502-9817
Email: bnelson@jhmi.edu
School of Medicine Address: Room 151 Cancer Research Bldg., 1650 Orleans Street, Baltimore, MD 21231
Cellular defenses against carcinogens; cellular responses to DNA damage; DNA methylation and epigenetic gene silencing; inflammation and prostatic carcinogenesis.
Normal and neoplastic cells respond to genome integrity threats in a variety of different ways. Furthermore, the nature of these responses are critical both for cancer pathogenesis and for cancer treatment. DNA damaging agents activate several signal transduction pathways in damaged cells which trigger cell fate decisions such as proliferation, genomic repair, differentiation, and cell death. For normal cells, failure of a DNA damaging agent (i.e., a carcinogen) to activate processes culminating in DNA repair or in cell death might promote neoplastic transformation. For cancer cells, failure of a DNA damaging agent (i.e., an antineoplastic drug) to promote differentiation or cell death might undermine cancer treatment.
Our laboratory has discovered the most common known somatic genome alteration in human prostatic carcinoma cells. The DNA lesion, hypermethylation of deoxycytidine nucleotides in the promoter of a carcinogen-defense enzyme gene, appears to result in inactivation of the gene and a resultant increased vulnerability of prostatic cells to carcinogens. Studies underway in the laboratory have been directed at characterizing the genomic abnormality further, and at developing methods to restore expression of epigenetically silenced genes and/or to augment expression of other carcinogen-defense enzymes in prostate cells as prostate cancer prevention strategies.
Another major interest pursued in the laboratory is the role of chronic or recurrent inflammation as a cause of prostate cancer. Genetic studies of familial prostate cancer have identified defects in genes regulating host inflammatory responses to infections. A newly described prostate lesion, proliferative inflammatory atrophy (PIA), appears to be an early prostate cancer precursor. Current experimental approaches feature induction of chronic prostate inflammation in laboratory mice and rats, and monitoring the consequences on the development of PIA and prostate cancer.
Representative Publications:
- Agoston, A.T., Argani, P., Yegnasubramanian, S., De Marzo, A.M., Ansari-Lari, M.A., Hicks, J.L., Davidson, N.E., and Nelson, W.G. Increased protein stability causes DNA methyltransferase 1 dysregulation in breast cancer, J. Biol. Chem. 280: 18302-18310, 2005. Pub Med Reference
- Drake, C.G., Doody, A.D., Mihalyo, M.A., Huang, C.T., Kelleher, E., Ravi, S., Hipkiss, E.L., Flies, D.B., Kennedy, E.P., Long, M., McGary, P.W., Coryell, L., Nelson, W.G., Pardoll, D.M., and Adler, A.J. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen, Cancer Cell 7(3): 239-249, 2005. Pub Med Reference
Bastian, P.J., Palapattu, G.S., Lin, X., Yegnasubramanian, S., Mangold, L.A., Trock, B., Eisenberger, M.A., Partin, A.W., and Nelson, W.G. Preoperative serum DNA GSTP1 CpG island hypermethylation and the risk of early prostate-specific antigen recurrence following fadical prostatectomy. Clin. Cancer Res. 11(11): 4037-4043, 2005. Pub Med Reference
Ouyang, X., DeWeese, T.L., Nelson, W.G., and Abate-Shen, C. Loss-of-function of Nkx3.1 promotes increased oxidative damage in prostate carcinogenesis. Cancer Res. 65: 6773-6779, 2005. Pub Med Reference
Lee, B.H., Yegnasubramanian, S., Lin, X., and Nelson, W.G. Procainamide is a specific inhibitor of DNA methyltransferase 1. J. Biol. Chem. 280(49): 40749-40756, 2005. Pub Med Reference
Yegnasubramanian, S., Lin, X., Haffner, M.C., De Marzo, A.M., and Nelson, W.G. Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes (COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation. Nucl. Acids Res. 34(3): e19, 2006. Pub Med Reference
Nakai, Y., Nelson, W.G., and De Marzo, A.M. The dietary charred meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) acts as both an initiator and tumor promoter in the rat ventral prostate. Cancer Res. 67: 1378-1384, 2007. Pub Med Reference
Agoston, A.T., Argani, P., Hicks, J.L., De Marzo, A.M., and Nelson, W.G. RB pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase promoting complex. Am. J. Pathol. 170: 1585-1593, 2007. Pub Med Reference
Other graduate programs in which Dr. Nelson participates:
Cellular and Molecular Medicine Graduate Program
Anti-Cancer Drug Development Program
