Mammary-derived growth inhibitor (MDGI) is a tumor suppressor gene that is maximally expressed in terminally differentiated mammary epithelial cells. The MDGI gene is silenced in human breast cancer cell lines and in many primary human and experimental breast tumors. We demonstrate that the antiestrogens 4-hydroxytamoxifen (4-OH tamoxifen) and ICI 182780 (ICI) stimulate MDGI expression in vitro. Dose-dependent MDGI mRNA accumulation was observed when ICI was added to the culture medium of mammary explants. Both 4-OH tamoxifen and ICI stabilized MDGI mRNA without affecting the transcription rate of the MDGI gene. Under estrogen-free conditions, the half-life of MDGI mRNA in control explants was approximately 6 h. This half-life was increased to 7.5 h in the presence of 10(-7) M 4-OH tamoxifen and to greater than 12 h in the presence of 10(-7) M ICI. There was a positive correlation between the antiproliferative activity of antiestrogens and their ability to stabilize MDGI mRNA. The up-regulation of expression of the MDGI tumor suppressor gene in normal breast tissue by antiestrogens may contribute to the protective activity of these compounds that is seen in mammary gland carcinogenesis experimental systems and to the decreased risk of contralateral cancer that is seen in women receiving tamoxifen therapy.