Background: Overexpression of transforming growth factor (TGF)-β-has been reported in human breast carcinomas resistant to antiestrogen tamoxifen, but the role of TGF-β in this resistant phenotype is unclear. We investigated whether inhibition of TGF-β2, which is overexpressed in LCC2 tamoxifen-resistant human breast cancer cells, could modify antiestrogen resistance. Methods: TGF-β2 expression was evaluated in LCC2 cells and tamoxifen-sensitive LCC1 cells by northern blot analysis. Secreted TGF-β activity was quantified by use of an 125I-TGF-β competitive radioreceptor assay. Sensitivity to tamoxifen was measured in a soft agarose colony- forming assay and in a xenograft model in nude and beige/nude mice. Natural killer (NK) cell cytotoxicity was measured by 51Cri release from LCC1 and LCC2 cell targets coincubated with human peripheral blood mononuclear cells. Decrease in TGF-β2 expression in LCC2 cells was achieved by treatment with antisense oligodeoxynucleotides and confirmed by TGF-β2 immunoblot analysis. Results and Conclusions: The proliferative response of LCC2 cells to tamoxifen in vitro was not altered by TGF-β neutralizing antibodies. However, established LCC2 tumors in nude mice treated with tamoxifen plus TGF-β antibodies failed to grow, whereas tumors treated with tamoxifen plus a control antibody continued to proliferate. This reversal of tamoxifen resistance by TGF-β antibodies did not occur in beige/nude mice, which lack NK-cell function, suggesting that immune mechanisms may be involved in the antitumor effects of tamoxifen. Antisense TGF-β2 oligodeoxynucleotides enhanced the NK sensitivity of LCC2 cells in the presence of tamoxifen. Finally, LCC1 tumors were markedly more sensitive to tamoxifen in NK-active than in NK-deficient mice. Implications: These data suggest that host NK function mediates, in part, the antitumor effect of tamoxifen and that TGF- β2 may abrogate this mechanism, thus contributing to tamoxifen resistance.