Research Overview
Our laboratory is interested in the connection between chronic inflammation and cancer with an emphasis on prostaglandin (PG) biology. A multifaceted approach is used. First, human cancers, premalignant lesions and chronic inflammatory states, e.g., ulcerative colitis, are identified in which the expression of enzymes involved in PG biosynthesis (cyclooxygenase-2, COX-2), catabolism (15-hydroxyprostaglandin dehydrogenase) or transport
(PGT) is deregulated. A second goal is to elucidate the signal transduction pathways that control the expression of these genes in normal and diseased tissues. Studies are also ongoing to define the mechanisms by which PGs stimulate the formation and progression of tumors. One major focus is hormone receptor-positive breast cancer. We are attempting to define the signaling pathway by which PGE2 induces cytochrome P450 aromatase, the enzyme that catalyzes the synthesis of estrogens from androgens.
Complementary experiments are being done to evaluate the role of dietary factors, e.g., fat and obesity as determinants of aromatase expression. The role of PGs in epithelial-mesenchymal transition is being determined in both colon and breast models. These mechanistic studies are complemented by preclinical pharmacological and genetic studies in animal models to determine whether targeting specific molecules involved in PG synthesis, e.g., COX-1 or mPGES-1, can impact on tumor formation or growth. In related work, studies are being done to identify biomarkers that may prove useful for the early detection of smoking-related lung injury or help to define the prognosis of cancer patients. Finally, given the link between chronic colitis and colon cancer, we are attempting to identify genes that play key roles in colorectal mucosal homeostasis. This line of investigation could lead to novel approaches to prevent or treat colorectal cancer.
