AntiestrogenModulationof the Growthand Propertiesof Ovarian Autonomousand Ovarian-DependentMammaryTumors in Rat&

Breast cancer probably consists of a spectrum of diseases in terms of its hormonal dependence, as evidenced by the responses of patients to endocrine therapy. It is generally assumed that hormone-dependent breast cancers, which me spond to ovariectomy, would also respond to antiestrogen therapy. Studies in humans indicate a good correlation be tween the presence of estrogen receptor and response to hormone ablative (ovariectomy) or additive hormonal or anti hormonal (such as antiestrogen) therapy (28). Yet it is occa sionally found (16) that some patients, whose tumors appear to lack estrogen receptors (based upon cytoplasmic receptor binding assays), do respond to antiestrogen therapy and, like wise, some patients that do not respond to ovariectomy me spond to subsequent antiestrogen treatment or vice versa. Antiestrogens are nonsteroidal triphenylethylene-type com pounds which antagonize a variety of estrogen-stimulated proc esses (18). Previous studies have shown that these compounds are capable of controlling the growth of hormone-dependent DMBA3-induced rat mammary tumors (8, 14, 17, 21 , 34), some human breast cancer cell lines (26, 36), and human breast cancers (2, 12, 13) in clinical trials. Little information is available, however, on the possible ef fects of antiestrogens on the growth of mammary tumors which are recalcitrant to endocrine ablation. Hence, the aim of this study was 2-fold: (a) to determine whether DMBA-induced mammary tumors unresponsive to ovariectomy would be caused to regress by antiestrogens and, conversely, whether tumors unresponsive to antiestrogen treatment would regress upon ovariectomy; and (b) to compare the effects of antiestro gens on the growth and biochemistry of ovarian-dependent DMBA-induced mammary tumors and the ovarian-autonomous but estrogen-sensitive R3230AC mammary adenocarcinoma (15). We find that in the DMBA mammary tumor system, although the majority of tumors are effectively regressed by ovariectomy or antiestrogen treatment, the tumors that respond partially to antiestrogen treatment or ovariectomy, i.e., are growth arrested or stabilized, may be further benefited by subsequent treatment