Transactivation of ErbB-2 induced by tumor necrosis factor alpha promotes NF-kappaB activation and breast cancer cell proliferation.
Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine which, acting locally, induces tumor growth. Accumulating evidence, including our findings, showed that TNFalpha is mitogenic in breast cancer cells in vitro and in vivo. In the present study, we explored TNFalpha involvement on highly aggressive ErbB-2-overexpressing breast cancer cells. We found that TNFalpha induces ErbB-2 phosphorylation in mouse breast cancer C4HD cells and in the human breast cancer cell lines SK-BR-3 and BT-474. ErbB-2 phosphorylation at Tyr877 residue was mediated by TNFalpha-induced c-Src activation. Moreover, TNFalpha promoted ErbB-2/ErbB-3 heterocomplex formation, Akt activation and NF-kappaB transcriptional activation. Inhibition of ErbB-2 by addition of AG825, an epidermal growth factor receptor/ErbB-2-tyrosine kinase inhibitor, or knockdown of ErbB-2 by RNA interference strategy, blocked TNFalpha-induced NF-kappaB activation and proliferation. However, the humanized monoclonal antibody anti-ErbB-2 Herceptin could not inhibit TNFalpha ability to promote breast cancer growth. Interestingly, our work disclosed that TNFalpha is able to transactivate ErbB-2 and use it as an obligatory downstream signaling molecule in the generation of mitogenic signals. As TNFalpha has been shown to be present in the tumor microenvironment of a significant proportion of human infiltrating breast cancers, our findings would have clinical implication in ErbB-2-positive breast cancer treatment.
Rivas
Martín A
MA
Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires C1428ADN, Argentina.
Tkach
Mercedes
M
Beguelin
Wendy
W
Proietti
Cecilia J
CJ
Rosemblit
Cinthia
C
Charreau
Eduardo H
EH
Elizalde
Patricia V
PV
Schillaci
Roxana
R
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D009363:Neoplasm Proteins; D011494:Protein Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D014409:Tumor Necrosis Factor-alpha; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse