In the 1960s and 1970s, antiestrogenicity was correlated with antitumor activity. However, the finding that nonsteroidal antiestrogens expressed increased estrogenic properties, i.e., vaginal cornification and increased uterine weight in the mouse, raised questions about the reasons for the species specificity. One obvious possibility was species-specific metabolism, i.e., the mouse converts antiestrogens to estrogens via novel metabolic pathways. However, no species-specific metabolic routes to known estrogens were identified but knowledge of the mouse model created a new dimension for study that ultimately led to the recognition of the target site-specific actions of antiestrogens. This concept was subsequently referred to as selective estrogen receptor modulation (SERM) to describe the target site-specific effects of raloxifene (see 8.09 Raloxifene), an antiestrogen originally targeted for an application in breast cancer but now used, paradoxically, as a preventive for osteoporosis. Now the whole class of drugs is known as SERMs.
The estrogen receptor-positive breast cancer cell line MCF7110 can be heterotransplanted to immune-deficient athymic mice but the cells will only grow into tumors with estrogen support.123 Paradoxically, tamoxifen, an estrogen in the mouse, does not support tumor growth but stimulates mouse uterine growth with the same spectrum of tamoxifen metabolites present in both the uterus and the human tumor.195 To explain the selective actions of tamoxifen in different targets of the same host, it was suggested that the estrogen receptor complex could be interpreted as a stimulatory or inhibitory signal at different sites. The concept was consolidated with experimental evidence from two further models. First, tamoxifen and raloxifene maintain bone density in the ovariectomized rat but both compounds inhibit estradiol-stimulated uterine weight and prevent carcinogen-induced mammary tumorigen-esis.122,196 Second, the finding that tamoxifen would partially stimulate the growth of a human endometrial carcinoma transplanted into athymic mice allowed the investigation of two human tumors bitransplanted in the same mouse to determine whether tamoxifen could inhibit estrogen-stimulated growth of two tumors in the same host equally. Tamoxifen demonstrated target site specificity: breast tumor growth was controlled but endometrial tumors continued to grow.197 Again, the spectrum of tamoxifen metabolites was consistent in all target tissues despite the contrasting biological responses, so it was concluded that the estrogen receptor complexes must be interpreted differently in different target tissues.
The laboratory principle of selective estrogen receptor modulation translated to the clinic with the findings that tamoxifen maintained bone density198 and lowered circulating cholesterol.199 These were extremely important findings because there were justifiable concerns that tamoxifen, an 'antiestrogen,' might prevent breast cancer but increase risks for osteoporosis and coronary heart disease. The beneficial effects of SERM action on bones and circulating cholesterol were important to advance clinical studies testing the worth of tamoxifen as a chemopreventive in high-risk women. Additionally, the recognition that tamoxifen increases the risk of endometrial cancer was an advantage for screening volunteers for trials. Nevertheless, the reports of carcinogenicity associated with tamoxifen naturally created major problems for recruitment to chemoprevention trials.
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