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

Carlos L. Arteaga, Katri M. Koli, Teresa C. Dugger, Robert Clarke

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)46-53
Number of pages8
JournalJournal of the National Cancer Institute
Volume91
Issue number1
StatePublished - Jan 6 1999

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Transforming Growth Factors
Tamoxifen
Neutralizing Antibodies
Breast Neoplasms
Nude Mice
Estrogen Receptor Modulators
Oligodeoxyribonucleotides
Natural Killer Cells
Antibodies
Neoplasms
Radioligand Assay
Heterografts
Northern Blotting
Sepharose
Blood Cells

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Reversal of tamoxifen resistance of human breast carcinomas in Vivo by neutralizing antibodies to transforming growth factor-β. / Arteaga, Carlos L.; Koli, Katri M.; Dugger, Teresa C.; Clarke, Robert.

In: Journal of the National Cancer Institute, Vol. 91, No. 1, 06.01.1999, p. 46-53.

Research output: Contribution to journalArticle

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abstract = "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.",
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