Paul J. Goodfellow, Ph.D.

DEPARTMENT OF Surgery
Keywords: cancer, DNA, genetics, gene expression

Our laboratory is investigating the genetic alterations that underlie development of uterine endometrial cancers. Endometrial cancer is the most common gynecologic malignancy in the United States. Like many cancers, uterine endometrial cancers are hormonally- responsive tumors. The genetic defects that are associated with the phenotypic progression from normal endometrium to carcinoma are elucidated through direct examination of primary human and mouse tumor tissues and precursor lesions. The lab’s efforts focus on the characterization of how changes in methylation of key regulatory sequences contribute to the cancer state, defining the inherited and acquired causes of defective DNA mismatch repair and determining how loss of DNA mismatch repair contributes to genotypic progression.

Endometrial, colon and other tumors with defective DNA mismatch repair accumulate large numbers of mutations. However, the genes that acquire mutations as a result of loss of mismatch repair remain elusive. We are attempting to determine how defective mismatch influences phenotypic and genotypic progression using a mouse model. Tumors are promoted with the synthetic estrogen, DES, in mice in which the Mlh1 DNA mismatch repair gene has been knocked out. Expression profiling in cancers and precancerous lesions provides candidate genes that are verified in mouse tumors, and their role in disease validated in human cancers.