Transactivation of ErbB-2 induced by tumor necrosis factor α promotes NF-κB activation and breast cancer cell proliferation
- 237 Downloads
Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine which, acting locally, induces tumor growth. Accumulating evidence, including our findings, showed that TNFα is mitogenic in breast cancer cells in vitro and in vivo. In the present study, we explored TNFα involvement on highly aggressive ErbB-2-overexpressing breast cancer cells. We found that TNFα 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 TNFα-induced c-Src activation. Moreover, TNFα promoted ErbB-2/ErbB-3 heterocomplex formation, Akt activation and NF-κB 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 TNFα-induced NF-κB activation and proliferation. However, the humanized monoclonal antibody anti-ErbB-2 Herceptin could not inhibit TNFα ability to promote breast cancer growth. Interestingly, our work disclosed that TNFα is able to transactivate ErbB-2 and use it as an obligatory downstream signaling molecule in the generation of mitogenic signals. As TNFα 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.
KeywordsErbB-2 TNFα Herceptin c-Src
This work was supported by grants IDB 1728/OC-AR PICT 2006 0211 and PICT 2004 05-25301, both from the National Agency of Scientific Promotion of Argentina, PIP 5391 from the Argentine National Council of Scientific Research (CONICET) and by Oncomed-Reno CONICET 1819/03, from the Henry Moore Institute of Argentina and by grant KG090250 from the Susan G. Komen for the Cure. The authors wish to thank Dr Alfredo A. Molinolo (NIH, Bethesda, MD) for his constant help and support. We thank Dr C. Lanari for providing the MPA-induced mammary tumor model.
- 2.Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC Jr (1993) Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression. Cancer Res 53:1939–1944PubMedGoogle Scholar
- 4.Rubio MF, Werbajh S, Cafferata EG, Quaglino A, Colo GP, Nojek IM, Kordon EC, Nahmod VE, Costas MA (2006) TNF-alpha enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B. Oncogene 25:1367–1377CrossRefPubMedGoogle Scholar
- 5.Rivas MA, Carnevale RP, Proietti CJ, Rosemblit C, Beguelin W, Salatino M, Charreau EH, Frahm I, Sapia S, Brouckaert P, Elizalde PV, Schillaci R (2008) TNFalpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappaB-dependent pathways. Exp Cell Res 314:509–529CrossRefPubMedGoogle Scholar
- 16.Yamauchi T, Yamauchi N, Ueki K, Sugiyama T, Waki H, Miki H, Tobe K, Matsuda S, Tsushima T, Yamamoto T, Fujita T, Taketani Y, Fukayama M, Kimura S, Yazaki Y, Nagai R, Kadowaki T (2000) Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer. J Biol Chem 275:33937–33944CrossRefPubMedGoogle Scholar
- 18.Lee CW, Lin CC, Lin WN, Liang KC, Luo SF, Wu CB, Wang SW, Yang CM (2007) TNF-alpha induces MMP-9 expression via activation of Src/EGFR, PDGFR/PI3K/Akt cascade and promotion of NF-kappaB/p300 binding in human tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292:L799–L812CrossRefPubMedGoogle Scholar
- 20.Chen WN, Woodbury RL, Kathmann LE, Opresko LK, Zangar RC, Wiley HS, Thrall BD (2004) Induced autocrine signaling through the epidermal growth factor receptor contributes to the response of mammary epithelial cells to tumor necrosis factor alpha. J Biol Chem 279:18488–18496CrossRefPubMedGoogle Scholar
- 22.Labriola L, Salatino M, Proietti CJ, Pecci A, Coso OA, Kornblihtt AR, Charreau EH, Elizalde PV (2003) Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. Mol Cell Biol 23:1095–1111CrossRefPubMedGoogle Scholar
- 39.Singh S, Shi Q, Bailey ST, Palczewski MJ, Pardee AB, Iglehart JD, Biswas DK (2007) Nuclear factor-kappaB activation: a molecular therapeutic target for estrogen receptor-negative and epidermal growth factor receptor family receptor-positive human breast cancer. Mol Cancer Ther 6:1973–1982CrossRefPubMedGoogle Scholar
- 40.Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726CrossRefPubMedGoogle Scholar
- 41.Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, Arteaga CL (2007) Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 13:4909–4919CrossRefPubMedGoogle Scholar
- 42.Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, LoRusso P, Lombardi DP, Ben Ahmed S, Citrin DL, DeSilvio ML, Harris J, Westlund RE, Salazar V, Zaks TZ, Spector NL (2008) Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 26:1066–1072CrossRefPubMedGoogle Scholar