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Originally published In Press as doi:10.1074/jbc.M010499200 on February 28, 2001

J. Biol. Chem., Vol. 276, Issue 21, 17864-17870, May 25, 2001
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Nerve Growth Factor Stimulates Proliferation and Survival of Human Breast Cancer Cells through Two Distinct Signaling Pathways*

Simon DescampsDagger §, Robert-Alain ToillonDagger , Eric Adriaenssens§, Valérie Pawlowski§||, Simon M. Cool**, Victor Nurcombe**, Xuefen Le BourhisDagger , Bénoni BoillyDagger , Jean-Philippe Peyrat||, and Hubert HondermarckDagger Dagger Dagger

From the Dagger  Equipe Facteurs de Croissance, UPRES EA-1033 Biologie du Développement, Université des Sciences et Technologies de Lille, 59655 Villeneuve d' ASCQ France, the  Immunopathologie Cellulaire des Maladies Infectieuses, CNRS, UMR 8527, Institut de Biologie de Lille, 59000 France, the ** Department of Anatomical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia, and the || Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, 59020 Lille, France

We show here that the neurotrophin nerve growth factor (NGF), which has been shown to be a mitogen for breast cancer cells, also stimulates cell survival through a distinct signaling pathway. Breast cancer cell lines (MCF-7, T47-D, BT-20, and MDA-MB-231) were found to express both types of NGF receptors: p140trkA and p75NTR. The two other tyrosine kinase receptors for neurotrophins, TrkB and TrkC, were not expressed. The mitogenic effect of NGF on breast cancer cells required the tyrosine kinase activity of p140trkA as well as the mitogen-activated protein kinase (MAPK) cascade, but was independent of p75NTR. In contrast, the anti-apoptotic effect of NGF (studied using the ceramide analogue C2) required p75NTR as well as the activation of the transcription factor NF-kB, but neither p140trkA nor MAPK was necessary. Other neurotrophins (BDNF, NT-3, NT-4/5) also induced cell survival, although not proliferation, emphasizing the importance of p75NTR in NGF-mediated survival. Both the pharmacological NF-kappa B inhibitor SN50, and cell transfection with IkBm, resulted in a diminution of NGF anti-apoptotic effect. These data show that two distinct signaling pathways are required for NGF activity and confirm the roles played by p75NTR and NF-kappa B in the activation of the survival pathway in breast cancer cells.

* This work was supported in part by a grant from the Ligue Nationale Contre le Cancer (Comité du Nord) and by the French Ministry of Research and Education.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipients of an Association pour la Recherche sur la Cancer fellowship.

Dagger Dagger To whom correspondence should be addressed: EA-1033, batiment SN3, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq cedex, France. Tel.: 33-3-20-43-40-97; Fax: 33-3-20-43-40-38; E-mail: hubert.hondermarck@univ-lille1.fr.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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