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

Arteaga CL, Koli KM, Dugger TC, Clarke R
J Natl Cancer Inst. 1999 91 (1): 46-53

PMID: 9890169 · DOI:10.1093/jnci/91.1.46

BACKGROUND - Overexpression of transforming growth factor (TGF)-beta has been reported in human breast carcinomas resistant to antiestrogen tamoxifen, but the role of TGF-beta in this resistant phenotype is unclear. We investigated whether inhibition of TGF-beta2, which is overexpressed in LCC2 tamoxifen-resistant human breast cancer cells, could modify antiestrogen resistance.

METHODS - TGF-beta2 expression was evaluated in LCC2 cells and tamoxifen-sensitive LCC1 cells by northern blot analysis. Secreted TGF-beta activity was quantified by use of an 125I-TGF-beta 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 51Cr release from LCC1 and LCC2 cell targets coincubated with human peripheral blood mononuclear cells. Decrease in TGF-beta2 expression in LCC2 cells was achieved by treatment with antisense oligodeoxynucleotides and confirmed by TGF-beta2 immunoblot analysis.

RESULTS AND CONCLUSIONS - The proliferative response of LCC2 cells to tamoxifen in vitro was not altered by TGF-beta neutralizing antibodies. However, established LCC2 tumors in nude mice treated with tamoxifen plus TGF-beta antibodies failed to grow, whereas tumors treated with tamoxifen plus a control antibody continued to proliferate. This reversal of tamoxifen resistance 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 antitumor effects of tamoxifen. Antisense TGF-beta2 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-beta2 may abrogate this mechanism, thus contributing to tamoxifen resistance.

MeSH Terms (24)

Animals Antibodies, Monoclonal Antineoplastic Agents, Hormonal Breast Neoplasms Cell Division Cytotoxicity, Immunologic Drug Resistance, Neoplasm Estrogen Antagonists Estrogens Female Humans Killer Cells, Natural Mice Mice, Nude Neoplasm Proteins Neoplasms, Hormone-Dependent Neoplasm Transplantation Oligonucleotides, Antisense RNA, Messenger RNA, Neoplasm Tamoxifen Transforming Growth Factor beta Tumor Cells, Cultured Tumor Stem Cell Assay

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