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Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN

Oncogene volume 20, pages 1287–1299 (2001)Cite this article

Abstract

The Nuclear Factor (NF)-κB family of transcription factors controls expression of genes which promote cell growth, survival, and neoplastic transformation. Recently we demonstrated aberrant constitutive activation of NF-κB in primary human and rat breast cancer specimens and in cell lines. Overexpression of the epidermal growth factor receptor (EGFR) family member Her-2/neu, seen in approximately 30% of breast cancers, is associated with poor prognosis. Previously, Her-2/neu has been shown to signal via a phosphatidylinositol 3 (PI3)-kinase to Akt/protein kinase B (PKB) pathway. Since this signaling pathway was recently shown to activate NF-κB, here we have tested the hypothesis that Her-2/neu can activate NF-κB in breast cancer. Overexpression of Her-2/neu and EGFR-4 in Ba/F3 cells led to constitutive PI3- and Akt kinase activities, and induction of classical NF-κB (p50/p65). Similarly, a tumor cell line and tumors derived from MMTV-Her-2/neu transgenic mice displayed elevated levels of classical NF-κB. Engagement of Her-2/neu receptor downregulated the level of NF-κB. NF-κB binding and activity in the cultured cells was reduced upon inhibition of the PI3- to Akt kinase signaling pathway via ectopic expression of kinase inactive mutants, incubation with wortmannin, or expression of the tumor suppressor phosphatase PTEN. Inhibitors of calpain, but not the proteasome, blocked IκB-α degradation. Inhibition of Akt did not affect IKK activity. These results indicate that Her-2/neu activates NF-κB via a PI3- to Akt kinase signaling pathway that can be inhibited via the tumor suppressor PTEN, and is mediated by calpain rather than the IκB kinase complex.

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Acknowledgements

We thank N Rice, C Rich, J Foster, W Ogawa, J Dixon, F Mercurio, ZG Rawadi and M Karin for generously providing antibody or cloned DNA. We thank D Stern, P Leder, W Muller and M Michelman for generously providing the Ba/F3 and MMTV-c-neu cell lines. We thank D Sloneker for assistance in preparation of this manuscript. This work was supported by grants from the Department of Army DAMD 17-98-1 (GE Sonenshein), and the NIH/NCI CA 82742 (GE Sonenshein), CA78616 (M Arsura), the Charlotte Geyer Foundation (M Arsura), and the Association pour la Recherche sur le Cancer (R Romieu-Mourez) and Fondation Bettencourt-Schueller (R Romieu-Mourez).

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  1. Marcello Arsura

    Present address: Department of Pharmacology, University of Tennessee, Memphis, 38163, TN, USA

Authors and Affiliations

  1. Department of Biochemistry and the Program in Research on Women's Health, Boston University Schools of Medicine, Boston, 02118, Massachusetts, MA, USA

    Stefania Pianetti, Marcello Arsura, Raphaëlle Romieu-Mourez & Gail E Sonenshein

  2. Vanderbilt University, Nashville, 37232, Tennessee, TN, USA

    Robert J Coffey

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Pianetti, S., Arsura, M., Romieu-Mourez, R. et al. Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN. Oncogene 20, 1287–1299 (2001). https://doi.org/10.1038/sj.onc.1204257

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