Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy. A sustained release of tamoxifen, which produced decreasing serum levels of this drug (24 to 4 ng/mL) over 6 months, suppressed mammary tumorigenesis in virgin or once pregnant C3H/OUJ female mice. Tamoxifen was consistently more effective than early ovariectomy, which only delayed tumorigenesis. Tamoxifen prevented the stimulatory action of cyclical (alternate-month) progesterone administration on mouse mammary tumorigenesis. However, when tamoxifen treatment (12 months) was stopped, progesterone treatment initiated tumorigenesis. In contrast, when long-term tamoxifen treatment was stopped in mice that had not undergone ovariectomy, and estrous cycle returned, the majority of these mice remained tumor free. A comparison of different durations (3, 6, and 12 months) of tamoxifen treatment of virgin mice, starting at approximately 4 months of age, showed an equivalent effect on mammary tumorigenesis. All virgin mice developed tumors by 18 months of age, whereas 80% of the tamoxifen-treated mice were tumor free. Nevertheless, cyclical progesterone administration caused rapid development of tumors after 3 months of tamoxifen treatment; only 15% of these mice were tumor free at 18 months. Cyclical progesterone administration caused an increase in tumorigenesis after 6 months of tamoxifen treatment; 50% of these mice were tumor free at 18 months of age. These data demonstrate the efficacy of tamoxifen to suppress mouse mammary tumorigenesis and demonstrate that continuous tamoxifen therapy is necessary to prevent the development of tumors by progesterone, a stimulatory hormone. 