title: Reversal of tamoxifen resistance of human breast carcinomas in vivo by neutralizing antibodies to transforming growth factor-beta.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt Cancer Center, Department of Veterans Affairs Medical Center, Nashville, TN 37232-5536, USA. carlos.arteaga@mcmail.vanderbilt.edu
authors.forename: C L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: K M
authors.initials: KM
authors.lastname: Koli
authors.forename: T C
authors.initials: TC
authors.lastname: Dugger
authors.forename: R
authors.initials: R
authors.lastname: Clarke
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000911:Antibodies, Monoclonal; D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D004967:Estrogens; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016212:Transforming Growth Factor beta; D013629:Tamoxifen