The chemotherapeutic management of advanced breast cancer is suboptimal, and results have plateaued in recent years. Investigation of new treatment approaches is warranted. Combined chemoendocrine therapy is one such approach, although results of this strategy to date have not been especially promising. The lack of an additive effect in some studies might be partially explained by an unfavorable interaction between the endocrine therapy and the cytotoxic therapy. Endocrine therapy slows breast cancer cell proliferation, and on a cell kinetic basis, may reduce chemosensitivity to certain drugs. In this proposal the mechanisms by which endocrine manipulation with estrogen withdrawal or with antiestrogens causes tumor regression will be studied using cultured human breast cancer cells, and cultured cell growing as subcutaneous tumors in athymic nude mice. Studies will be performed to determine whether endocrine therapy is lethal for breast cancer cells, or whether it simply slows their proliferation and induces an "inactive" state. The importance of a functioning immune response to the tumor regression observed with hormone manipulation will be investigated, to test the hypothesis that inhibition of tumor cell proliferation coupled with an intact immune response are both required for maximal tumor regression with endocrine treatment. If inhibition of cell proliferation reduces chemosensitivity to certain drugs, then, perhaps, transient stimulation of the tumor with "estrogen rescue" might result in an enhanced effect. The phenomenon of "estrogen rescue," which has been characterized in vitro in detail, will be studied in depth in vivo in the nude mouse tumor model. Binding to receptor, nuclear receptor processing, accumulation of mRNA, specific protein synthesis, and cell kinetic and growth alterations in response to estrogen replenishment of estrogen-deprived or antiestrogen-treated mice will be examined. When the timing of estrogen rescue has been defined, then the strategy of combined chemoendocrine therapy using estrogen rescue to stimulate the tumor in vivo will be studied to determine whether this technique can be exploited to increase chemosensitivity. These studies will provide important information on the antitumor mechanisms of hormone manipulation, and should lead to more rational therapeutic strategies using combined chemoendocrine therapy.