Angela H. Brodie, Ph.D.
Laboratory of Steroid Regulation of Breast Cancer
The long-term interests of our research are estrogen biosynthesis, its regulation in the ovary and the importance of estrogen in breast cancer. To this end, we have developed selective aromatase inhibitors for the treatment of breast cancer and other diseases. Initially, we synthesized and evaluated a number of compounds which we subsequently found to inhibit estrogen biosynthesis. We demonstrated that the compounds inhibit ovarian aromatase and estrogen production, and cause mammary tumor regression in the rat. Studies with 4-OHA, the most potent compound, showed that treatment reduced the mid-cycle estrogen surge in female baboons and inhibited peripheral aromatization in male rhesus monkeys. Subsequently, we demonstrated that 4-OHA reduced peripheral plasma estrogen levels and caused significant tumor regression in postmenopausal patients with advanced metastatic breast cancer who had relapsed from conventional treatment. The compound has both oral and parenteral activity, has similar efficacy to tamoxifen and is without significant side effects in these patients. The compound has now been approved for the treatment of breast cancer in many countries world wide. Current research in our laboratory is focused on the effects of these compounds and newer non-steroidal inhibitors on estrogen responsive tissues. We are employing immunocytochemistry, in situ hybridization, reverse transcription-polymerase chain reaction and flow cytometry to determine expression of aromatase in the normal breast and breast cancer and the role of aromatase, and angiogenesis in the processes of tumor growth and development. We have recently developed a new animal model using stably transfected cDNA to express aromatase in breast cancer cells. This model is proving valuable to determine mechanisms of the effects of estrogens, aromatase inhibitors and other hormone antagonists on the molecular events involved in the growth of breast cancer and endometrial tissue.
Recent PublicationsBrodie AMH 1995 Aromatase inhibitors. In: Hormone-Dependent Cancer. Pasqualinin JR and Katzenellenbogen BS (eds). Molecular and Clinical Endocrinology, Marcell Dekker.
Yue W, Wang J, Savinov A, Brodie A 1995 The effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model. Cancer Research 55:3073-3077.
Lu Q, Nakamura J, Savinov A, Yue W, Weisz J, Dabbs DJ, Wolz G, Brodie A 1996 Expression of aromatase protein and messenger RNA in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. Endocrinology 137:3061-3068.
Nakamura J, Savinov A, LuQ, Brodie A 1996 Estrogen regulates vascular endothelial growth/permeability factor expression in DMBA induced rat mammary tumors. Endocrinology 137:5589-5596.
Yue W, Brodie A 1997 Mechanisms of the actions of aromatase inhibitors 4-OHA, fadrozole and aminoglutethimide on aromatase in JEG-3 cell cultures. Journal of Steroid Biochemistry Molecular Biology, in press.
