Laboratory models of breast and endometrial cancer to develop strategies for antiestrogen therapy

Laboratory models for breast and endometrial cancer have had an enormous impact on the clinical development of antiestrogens. Results from the DMBA-induced rat mammary cancer model has provided the scientific principles required to evaluate long-term adjuvant tamoxifen therapy. Similarly, the athymic mouse model allowed the identification of clinically relevant mechanisms of drug resistance to tamoxifen and a model system to test new agents for cross resistance. Additionally, the endometrial cancer model has allowed the identification of agents that cause a slight increase in the risk of endometrial cancer long before the data would have be available from clinical studies. However, it should be stressed that this model is really only relevant for agents to be tested as preventives in normal women. The risks of developing endometrial cancer during tamoxifen therapy are slight compared with the survival benefit in controlling breast cancer.Finally the discovery of the carcinogenic potential of tamoxifen in the rat liver, 20 years after it was first introduced into clinical practice, raises an interesting issue. If the studies of liver carcinogenicity had been completed and published in the early 1970's there would be no tamoxifen and tens of thousands of women with breast cancer would have died prematurely. In fact there would have been no incentive to develop new agents as alternatives to tamoxifen or following tamoxifen failure. Most importantly, we would not have any knowledge about the target-site or selective actions of antiestrogens. All the current interest in selective estrogen receptor modulators (SERMs) is based on the huge clinical data base obtained by studying tamoxifen. The success of tamoxifen as an agent that preserves bone density, lowers cholesterol and prevents contralateral breast cancer(43) has become a classic example of a multimechanistic drug. These concepts have acted as a catalyst to develop new agents for new applications. The laboratory studies of raloxifene(44-46)) provided the scientific rationale for the use of raloxifene as a preventive for osteoporosis(47)) but with the goal of preventing breast cancer in post-menopausal women(48,49)) (Fig 5). It is clear that the close collaboration between laboratory and clinical research has revolutionized the prospects for women's health care in the 21st century.