Laboratory models of breast cancer to aid the elucidation of antiestrogen action.

The historical development of carcinogen-induced rat mammary tumors is reviewed. Most work has been done with the polycyclic hydrocarbon dimethylbenz[a]anthracene (DMBA). Huggins was the first to describe a protocol for the routine production of DMBA-induced mammary tumors and demonstrated their ovarian dependency. Pearson found that DMBA-induced tumors could not grow during estrogen administration in hypophysectomized rats, and it was subsequently shown that estrogen-stimulated prolactin release is responsible for tumor growth. The antiestrogen tamoxifen has been used in the treatment of breast cancer and has been studied extensively in the DMBA-induced rat mammary carcinoma model. The complexities of tamoxifen's pharmacology in vivo suggested that the development of estrogen-responsive systems in vitro might facilitate an understanding of tamoxifen's mode of action. The description of estrogen-stimulated prolactin synthesis by primary culture of pituitary gland cells provided an opportunity to study the structure-activity relationships of antiestrogens. A model ("crocodile model") to describe the interaction of estrogens and antiestrogens is proposed. An estrogen will permit the conformation change in the receptor that is necessary to translate into prolactin synthesis. An antiestrogen wedges into the binding site on the receptor to prevent changes in protein conformation. As a result prolactin synthesis is inhibited. An extensive study of structure-activity relationships has been used to describe the nature of the ligand binding site of the estrogen receptor. The model can be used to predict the pharmacology of new agents.