Reversal of the antiproliferative effect of the antiestrogen tamoxifen by polyamines in breast cancer cells.

Numerous studies suggest a relationship between the action of hormones on their target tissues and the synthesis of polyamines. To evaluate the role of polyamines in the mediation of the effect of estrogen on the growth of experimental hormone-responsive mammary cancer, we investigated whether the cytotoxic effect of the antiestrogen tamoxifen could be rescued by exogenous administration of polyamines. When added to N-nitrosomethylurea-induced mammary tumors grown in soft agar in the presence of tamoxifen, putrescine, spermidine, and spermine were able to reverse the inhibitory effect of antiestrogens on colony formation in a dose-dependent fashion. In contrast, no effect on colony number was observed when polyamines were added in the absence of tamoxifen. These results indicate that in this system, the antitumor effect of tamoxifen is mediated through induction of polyamine depletion. Consequently, the data suggest that estrogens may stimulate mitogenesis of the N-nitrosomethylurea-induced mammary tumor through the polyamine pathway.