Abstract
Nuclear factor-κB (NF-κB) is usually maintained in an inactive form in the cytoplasm through its association with inhibitor of kappaB (IκB) proteins, and is activated upon stimulation of cells with a variety of signals. However, constitutive activation of NF-κB is observed in a number of cancers including breast cancer. The signaling pathways that are involved in constitutive NF-κB activation remain largely unknown. Using breast cancer cell lines derived from transgenic mice that overexpress specific oncogene/growth factors in the mammary gland, we show that heregulin but not her2/neu, c-Myc or v-Ha-ras plays a major role in constitutive NF-κB activation. Her2/neu potentiated tumor necrosis factor alpha (TNFα)-inducible NF-κB activation whereas c-Myc potentiated 12-o-tetracecanyolphorbol-13-acetate (TPA)-induced NF-κB activation. Heregulin-mediated NF-κB activation correlated with phosphorylation of epidermal growth factor receptor (EGFR) and ErbB3 but not her2/neu. Tryphostin AG1517, which inhibits heregulin-mediated phosphorylation of EGFR, her2/neu and ErbB3 reduced NF-κB activation. In contrast, emodin, which blocks phosphorylation of her2/neu by heregulin, failed to reduce NF-κB activation. These results suggest that heregulin induces NF-κB independent of her2/neu. PI3 kinase/AKT, protein kinase A (PKA) and IκB kinase appear to be downstream signaling molecules involved in NF-κB activation as specific inhibitors of these kinases but not inhibitors of ERK/MAP kinase or protein kinase C reduced heregulin-mediated NF-κB activation. Based on these results, we propose that heregulin increases the expression of pro-invasive, pro-metastatic and anti-apoptotic genes in cancer cells through autocrine activation of NF-κB, which leads to invasive and drug-resistant growth of breast cancer.
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Abbreviations
- NF-κB:
-
Nuclear factor-kappaB
- IκB:
-
Inhibitor of kappaB
- TNF:
-
Tumor necrosis factor
- IL-1:
-
Interleukin 1
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
- EGFR:
-
Epidermal growth factor receptor
- PKA:
-
Protein kinase A
- EMSA:
-
Electrophoretic mobility shift assay
References
Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF, Pietras RJ, Pisacane P, Sliwkowski MX, Slamon DJ . 1999 Oncogene 18: 6050–6062
Amundadottir LT, Leder P . 1998 Oncogene 16: 737–746
Baldwin AS . 2001 J. Clin. Invest. 107: 241–246
Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C, Dörken B . 1997 J. Clin. Invest. 100: 2961–2969
Barkett M, Gilmore TD . 1999 Oncogene 18: 6910–6924
Biswas DK, Cruz AP, Gansberger E, Pardee AB . 2000 Proc. Natl. Acad. Sci. USA 97: 8542–8547
Chen L, Fischle W, Verdin E, Greene WC . 2001 Science 293: 1653–1657
Clark GJ, Der CJ . 1995 Breast Cancer Res. Treat. 35: 133–144
Clarkson RW, Heeley JL, Chapman R, Aillet F, Hay RT, Wyllie A, Watson CJ . 2000 J. Biol. Chem. 275: 12737–12742
Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin Jr AS . 2000 Oncogene 19: 1123–1131
Dignam JD, Lebovitz RM, Roeder RG . 1983 Nucleic Acids Res. 11: 1475–1489
Dong G, Chen Z, Kato T, Van Waes C . 1999 Cancer Res. 59: 3495–3504
Escot C, Theillet C, Lidereau R, Spyratos F, Champene MH, Gest J, Callahan R . 1986 Proc. Natl. Acad. Sci. USA 83: 4834–4838
Fiddes RJ, Campbell DH, Janes PW, Sivertsen SP, Sasaki H, Wallasch C, Daly RJ . 1998 J. Biol. Chem. 273: 7717–7724
Ghosh S, May MJ, Kopp EB . 1998 Annu. Rev. Immunol. 16: 225–260
Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, Vartanian T . 2001 J. Biol. Chem. 276: 8865–8874
Harari D, Yarden Y . 2000 Oncogene 19: 6102–6114
Hehner SP, Hofmann TG, Droge W, Schmitz ML . 1999 J. Immunol. 163: 5617–5623
Kim DW, Sovak MA, Zanieski G, Nonet G, Romieu-Mourez R, Lau AW, Hafer LJ, Yaswen P, Stampfer M, Rogers AE, Russo J, Sonenshein GE . 2000 Carcinogenesis 21: 871–879
Klefstrom J, Arighi E, Littlewood T, Jaattela M, Saksela E, Evan GI, Alitalo K . 1997 EMBO J. 16: 7382–7392
Koul D, Yao Y, Abbruzzese JL, Yung WK, Reddy SA . 2001 J. Biol. Chem. 276: 11402–11408
Kroiher M, Miller MA, Steele RE . 2001 Bioessays 23: 69–76
Lee H, Maihle NJ . 1998 Oncogene 16: 3243–3252
Lupu R, Cardillo M, Cho C, Harris L, Hijazi M, Perez C, Rosenberg K, Yang D, Tang C . 1996 Breast Cancer Res. Treat. 38: 57–66
Madrid LV, Mayo MW, Reuther JY, Baldwin Jr AS . 2001 J. Biol. Chem. 276: 18934–18940
Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet Jr RJ, Sledge Jr GW . 1997 Mol. Cell. Biol. 17: 3629–3639
Newton TR, Patel NM, Bhat-Nakshatri P, Stauss CR, Goulet Jr RJ, Nakshatri H . 1999 J. Biol. Chem. 274: 18827–18835
Nozaki S, Sledge Jr GW, Nakshatri H . 2000 Biochem. Biophys. Res. Commun. 275: 60–62
Nozaki S, Sledge Jr GW, Nakshatri H . 2001 Oncogene 20: 2178–2185
Olayioye MA, Neve RM, Lane HA, Hynes NE . 2000 EMBO J. 19: 3159–3167
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB . 1999 Nature 401: 82–85
Patel NM, Nozaki S, Shortle NH, Bhat-Nakshatri P, Newton TR, Rice S, Gelfanov V, Boswell SH, Goulet Jr RJ, Sledge Jr GW, Nakshatri H . 2000 Oncogene 19: 4159–4169
Ravi R, Bedi GC, Engstrom LW, Zeng Q, Mookerjee B, Gelinas C, Fuchs EJ, Bedi A . 2001 Nat. Cell. Biol. 3: 409–416
Rayet B, Gelinas C . 1999 Oncogene 18: 6938–6947
Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin Jr AS . 1998 Genes Dev. 12: 968–981
Riese II DJ, Stern DF . 1998 Bioessays 20: 41–48
Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Traish AM, Mercurio F, Sonenshein GE . 2001 Cancer Res. 61: 3810–3818
Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M . 2001 Science 293: 1495–1499
Shattuck-Brandt RL, Richmond A . 1997 Cancer Res. 57: 3032–3039
Sizemore N, Leung S, Stark GR . 1999 Mol. Cell. Biol. 19: 4798–4805
Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM, Sonenshein GE . 1997 J. Clin. Invest. 100: 2952–2960
Sweeney C, Fambrough D, Huard C, Diamonti AJ, Lander ES, Cantley LC, Carraway III KL . 2001 J. Biol. Chem. 276: 22685–22698
Wang CY, Mayo MW, Baldwin Jr AS . 1996 Science 274: 784–787
Yen L, You XL, Al Moustafa AE, Batist G, Hynes NE, Mader S, Meloche S, Alaoui-Jamali MA . 2000 Oncogene 19: 3460–3469
Zhang L, Chang CJ, Bacus SS, Hung MC . 1995 Cancer Res. 55: 3890–3896
Zhong H, Voll RE, Ghosh S . 1998 Mol. Cell. 1: 661–671
Zhou BP, Hu MC, Miller SA, Yu Z, Xia W, Lin SY, Hung MC . 2000 J. Biol. Chem. 275: 8027–8031
Acknowledgements
We thank Drs Laufy Thora Amundadottir and Philip Leder for providing breast cancer cell lines from transgenic mice. We also thank Carmen R Stauss for technical assistance, Robert A Campbell for advice and David Chang for critical reading of the manuscript. This work is supported by grants from the American Cancer Society (RPG-00-122-01-TBE), American Institute for Cancer Research (00A407) and Phi Beta Psi Sorority (H Nakshatri).
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Bhat-Nakshatri, P., Sweeney, C. & Nakshatri, H. Identification of signal transduction pathways involved in constitutive NF-κB activation in breast cancer cells. Oncogene 21, 2066–2078 (2002). https://doi.org/10.1038/sj.onc.1205243
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DOI: https://doi.org/10.1038/sj.onc.1205243
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