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Molecular & Cellular Proteomics 6:1239-1247, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Proteomics Demonstration That Normal Breast Epithelial Cells Can Induce Apoptosis of Breast Cancer Cells through Insulin-like Growth Factor-binding Protein-3 and Maspin^*

Robert-Alain Toillon^,, Chann Lagadec^,,¶, Adeline Page^||, Valérie Chopin, Pierre-Eric Sautière^**, Jean-Marc Ricort, Jérôme Lemoine, Ming Zhang^¶¶, Hubert Hondermarck and Xuefen Le Bourhis^,||||

From the INSERM ERI-8 (JE 2488) "Signalisation des facteurs de croissance dans le cancer du sein. Protéomique fonctionnelle," ^|| Centre Commun de Mesure de Spectrométrie de Masse, and ^** CNRS FRE 2933, IFR 147, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq, France, CNRS UMR 8113, Ecole Normale Supérieure, 94230 Cachan, France, CNRS UMR 5180, Université Claude Bernard, 69622 Villeurbanne, France, and ^¶¶ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Normal breast epithelial cells are known to exert an apoptotic effect on breast cancer cells, resulting in a potential paracrine inhibition of breast tumor development. In this study we purified and characterized the apoptosis-inducing factors secreted by normal breast epithelial cells. Conditioned medium was concentrated by ultrafiltration and separated on reverse phase Sep-Pak C₁₈ and HPLC. The proapoptotic activity of eluted fractions was tested on MCF-7 breast cancer cells, and nano-LC-nano-ESI-MS/MS allowed the identification of insulin-like growth factor-binding protein-3 (IGFBP-3) and maspin as the proapoptotic factors produced by normal breast epithelial cells. Western blot analysis of conditioned media confirmed the specific secretion of IGFBP-3 and maspin by normal cells but not by breast cancer cells. Immunodepletion of IGFBP-3 and maspin completely abolished the normal cell-induced apoptosis of cancer cells, and recombinant proteins reproduced the effect of normal cell-conditioned medium on apoptosis of breast cancer cells. Together our results indicated that normal breast epithelial cells can induce apoptosis of breast cancer cells through IGFBP-3 and maspin. These findings provide a molecular hypothesis for the long observed inhibitory effect of normal surrounding cells on breast cancer development.

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