ABSTRACT
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of a class of compounds that includes other Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins, Polychlorinated dibenzofurans, and Polychlorinated biphenyls. This chapter describes their inhibition of 17ß-estradiol (estrogen, E2)-induced responses, the molecular mechanism of action of these chemicals, and the development of a new class of mechanism-based indirect antiestrogens for treatment of breast cancer. It primarily focuses on the antiestrogenic activity of AhR agonists response, which involves complex interactions between the AhR and ER signaling pathways. MCF-7 human breast cancer cells have been used extensively as an in vitro model for investigating E2-regulated responses and gene expression, effects, and mechanism of action of antiestrogens. Treatment with cells with E2 activates multiple cell cycle proteins and related activity and thereby offers multiple targets for the indirect antiestrogenic activity of TCDD. The major problems for development of clinically useful AhR-based antiestrogens are comparable to the design of other drugs.
