Reversal of tamoxifen resistance of human breast carcinomas in vivo by neutralizing antibodies to transforming growth factor-beta

Background: Overexpression of transforming growth factor (TGF)-beta has bee n reported in human breast carcinomas resistant to antiestrogen tamoxifen, but the role of TGF-beta in this resistant phenotype is unclear. We investi gated whether inhibition of TGF-beta 2, which is overexpressed in LCC2 tamo xifen-resistant human breast cancer cells, could modify antiestrogen resist ance, Methods: TGF-beta 2 expression was evaluated in LCC2 cells and tamoxi fen-sensitive LCC1 cells by northern blot analysis, Secreted TGF-beta activ ity was quantified by use of an I-125-TGF-beta competitive radioreceptor as say. 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 Cr-51 release from LCC1 and LCC2 ce ll targets coincubated with human peripheral blood mononuclear cells. Decre ase in TGF-beta 2 expression in LCC2 cells was achieved by treatment with a ntisense oligodeoxynucleotides and confirmed by TGF-beta 2 immunoblot analy sis, Results and Conclusions: The proliferative response of LCC2 cells to t amoxifen in vitro was not altered by TGF-P neutralizing antibodies. However , established LCC2 tumors in nude mice treated with tamoxifen plus TGF-beta antibodies failed to grow, whereas tumors Created with tamoxifen plus a co ntrol antibody continued to proliferate. This reversal of tamoxifen resista nce by TGF-beta antibodies did not occur in beige/nude mice, which lack NK- cell function, suggesting that immune mechanisms may be involved in the ant itumor effects of tamoxifen, Antisense TGF-beta 2 oligodeoxynucleotides enh anced the NK sensitivity of LCC2 cells in the presence of tamoxifen, Finall y, LCC1-tumors were markedly more sensitive to tamoxifen in NK-active than in NK-deficient mice. Implications: These data suggest that host NK functio n mediates, in part, the antitumor effect of tamoxifen and that TGF-beta 2 may abrogate this mechanism, thus contributing to tamoxifen resistance.