Development of Aromatase Inhibitors and Selective Aromatase Expression Regulators for Hormone Dependent Breast Cancer

Breast cancer is the most common cancer among women, and ranks second among cancer deaths in women. Approximately 60% of all breast cancer patients have hormone-dependent breast cancer, which contains estrogen receptors and requires estrogen for tumor growth. Aromatase, the enzyme responsible for estrogen biosynthesis, is a particularly attractive target in the treatment of hormone-dependent breast cancer. The development of aromatase inhibitors from isoflavone scaffold and selective aromatase expression regulators from COX-2 inhibitors for ER positive breast cancer are described in this study. The aromatase inhibitors synthesized in this study significantly inhibit the enzyme in human placenta microsomes and breast cancer cells. However, aromatase inhibitors inhibit aromatase activity in a global fashion and thus could adversely impact sites where estrogen is required for normal function. A new approach to reduce the risk of side effects is to develop agents that regulate aromatase expression in a tissue-specific manner. The expression of the aromatase gene is regulated in a tissue-specific manner by the alternative use of eight promoters. Furthermore, due to the unique organization of tissue-specific promoters, various promoters employ different signaling pathways and different transcription factors. Prostaglandin E2 (PGE2), the major product of cyclooxygenase-2 (COX-2), stimulates aromatase gene expression in breast cancer. This biochemical mechanism may explain epidemiological observations of the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer. Thus COX-2 inhibitors might be considered as the first generation of selective aromatase expression regulators. Sulfonanilide analogs of the COX-2 inhibitors NS-398 and nimesulide were synthesized, and the effect of these compounds on aromatase and COX-2 inhibition was investigated in breast cancer cells. The results suggest that these novel sulfonanilide analogs suppress aromatase activity by interfering with cAMP driven aromatase transcription in a COX-2 independent manner in breast cells. Future studies will focus on a more specific SAR study of these compounds and the possible molecular target(s) of the novel sulfonanilide analogs.