© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 1, 46-53,
January 6, 1999
© 1999 Oxford University Press
ARTICLES |
Reversal of Tamoxifen Resistance of Human Breast Carcinomas In Vivo by Neutralizing Antibodies to Transforming Growth Factor-ß
Affiliations of authors: C. L. Arteaga, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt Cancer Center, Department of Veteran Affairs Medical Center, Nashville, TN; K. M. Koli, T. C. Dugger, Department of Cell Biology, Vanderbilt University School of Medicine, Nashville; R. Clarke, Lombardi Cancer Center, Georgetown University, Washington, DC.
Correspondence to: Carlos L. Arteaga, M.D., Division of Medical Oncology, Vanderbilt University School of Medicine, 22nd Ave., S., 1956 TVC, Nashville, TN 37232-5536 (e-mail carlos.arteaga{at}mcmail.vanderbilt.edu).
BACKGROUND: Overexpression of transforming growth factor (TGF)-ß has been reported in human breast carcinomas resistant to antiestrogen tamoxifen, but the role of TGF-ß in this resistant phenotype is unclear. We investigated whether inhibition of TGF-ß2, which is overexpressed in LCC2 tamoxifen-resistant human breast cancer cells, could modify antiestrogen resistance. METHODS: TGF-ß2 expression was evaluated in LCC2 cells and tamoxifen-sensitive LCC1 cells by northern blot analysis. Secreted TGF-ß activity was quantified by use of an 125I-TGF-ß 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-ß2 expression in LCC2 cells was achieved by treatment with antisense oligodeoxynucleotides and confirmed by TGF-ß2 immunoblot analysis. RESULTS AND CONCLUSIONS: The proliferative response of LCC2 cells to tamoxifen in vitro was not altered by TGF-ß neutralizing antibodies. However, established LCC2 tumors in nude mice treated with tamoxifen plus TGF-ß antibodies failed to grow, whereas tumors treated with tamoxifen plus a control antibody continued to proliferate. This reversal of tamoxifen resistance by TGF-ß 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-ß2 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-ß2 may abrogate this mechanism, thus contributing to tamoxifen resistance.
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