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Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells

Breast Cancer Research 2008, 10:R101doi:10.1186/bcr2204

B¨¦reng¨¨re Marty1 , Virginie Maire1 , El¨¦onore Gravier1,2,3,6 , Guillem Rigaill1,7 , Anne Vincent-Salomon4 , Marion Kappler1 , Ingrid Lebigot4 , Fathia Djelti1 , Audrey Tourd¨¨s1 , Pierre Gestraud3,6 , Philippe Hup¨¦3,5,6 , Emmanuel Barillot3,6 , Francisco Cruzalegui8 , Gordon C Tucker8 , Marc-Henri Stern9 , Jean-Paul Thiery1,10 , John A Hickman8 and Thierry Dubois1
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Abstract
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Introduction
Basal-like carcinomas (BLCs) and human epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers that have the most aggressive clinical behaviour. In contrast to HER2+ carcinomas, no targeted therapy is currently available for the treatment of patients with BLCs. In order to discover potential therapeutic targets, we aimed to discover deregulated signalling pathways in human BLCs.
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Methods

In this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in 13 BLCs, and compared it with a control series of 11 hormonal receptor negative- and grade III-matched HER2+ carcinomas. The two tumour populations were first characterised by immunohistochemistry and gene expression. The PI3K pathway was then investigated by gene copy-number analysis, gene expression profiling and at a proteomic level using reverse-phase protein array technology and tissue microarray. The effects of the PI3K inhibition pathway on proliferation and apoptosis was further analysed in three human basal-like cell lines.
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Results

The PI3K pathway was found to be activated in BLCs and up-regulated compared with HER2+ tumours as shown by a significantly increased activation of the downstream targets Akt and mTOR (mammalian target of rapamycin). BLCs expressed significantly lower levels of the tumour suppressor PTEN and PTEN levels were significantly negatively correlated with Akt activity within that population. PTEN protein expression correlated significantly with PTEN DNA copy number and more importantly, reduced PTEN DNA copy numbers were observed specifically in BLCs. Similar to human samples, basal-like cell lines exhibited an activation of PI3K/Akt pathway and low/lack PTEN expression. Both PI3K and mTOR inhibitors led to basal-like cell growth arrest. However, apoptosis was specifically observed after PI3K inhibition.
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Conclusions

These data provide insight into the molecular pathogenesis of BLCs and implicate the PTEN-dependent activated Akt signalling pathway as a potential therapeutic target for the management of patients with poor prognosis BLCs.

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1    D¨¦partement de Transfert, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
2    D¨¦partement de Biostatistiques, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
3    INSERM U900, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
4    Service de Pathologie, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
5    CNRS UMR144, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
6    Ecole des Mines de Paris, 77300 Fontainebleau, France
7    Unit¨¦ de Math¨¦matiques et Informatique Appliqu¨¦es, UMR518, AgroParisTech/INRA, 75005 Paris, France
8    Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy sur Seine, France
9    INSERM U830, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
10  Current address: Institute of Molecular and Cell Biology, 61 Biopolis Drive (Proteos), 138673 Singapore
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http://breast-cancer-research.com/content/10/6/R101

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