Acetaminophen-induced proliferation of breast cancer cells involves estrogen receptors

Previous studies have shown that acetaminophen, a common analgesic/antipyre tic, induces proliferation of cultured breast cancer cells containing both estrogen and progesterone receptors (ER+/PR+). The main objective of this s tudy was to evaluate the involvement of ERs in this effect, First, the effe cts of therapeutic acetaminophen concentrations were compared in breast can cer cells with high ERs and in T47Dco cells with lower ERs, to determine if acetaminophen-induced proliferation depends on ER levels. Second, the effe cts of two antiestrogens (ICI 182,780 and 4'-hydroxytamoxifen on acetaminop hen-induced proliferation were determined in three human breast cancer cell lines: two ER+/PR+ (MCF7, T47D) and one ER-/PR- (MDA-MB-231). Third, ER bi nding assays were performed in MCF7 cells to determine if acetaminophen com peted with estradiol for binding to ERs. Proliferation endpoints monitored included percent cells in the DNA synthesis phase of the cell cycle, H-3-th ymidine incorporation into DNA, and cell number. Acetaminophen did not indu ce DNA synthesis in T47Dco cells, but did in cells with higher ER levels, s uggesting high ER levels are necessary for acetaminophen to induce prolifer ation. Antiestrogens inhibited acetaminophen-induced proliferation in ER+/P R+ cells while no effects were observed in ER-/PR- cells, further supportin g ER involvement. However, acetaminophen did not compete with estradiol for binding to ERs in ER+/PR+ cells. Collectively, these data suggest that ace taminophen induces breast cancer cell proliferation via ERs without binding to ERs like estradiol, The second purpose of this study was to determine i f acetaminophen is estrogenic/ antiestrogenic in vivo (uterotrophic assays) . Acetaminophen has no antiestrogenic/estrogenic activity in mice or rats u teri. (C) 1999 Academic Press.