Transcriptomics,Genomics

Dataset Information

52

Frequent PTEN genomic alterations and activated PI3K pathway in basal-like breast cancer


ABSTRACT: Introduction Basal-like (BLCs) and epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers which have the more aggressive clinical behavior. 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 searched for deregulated signaling pathways in human BLCs. Methods In this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in twelve BLCs, and compared it to a control series of eleven hormonal receptor negative- and grade III- matched HER2+ carcinomas. The two tumor populations were first characterized 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 PI3K inhibition pathway on proliferation and apoptosis was further analyzed in three human basal-like cell lines. Results The PI3K pathway was found to be activated in BLCs and up-regulated compared to HER2+ tumors as shown by a significantly increased activation of the downstream targets Akt and mTOR. BLCs expressed significantly lower levels of the tumor suppressor PTEN and PTEN levels correlated negatively in a significant manner 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. Similarly 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 observed specifically after PI3K inhibition. Overall design: The PI3K pathway was examined in 2 populations of highly proliferative, grade III, hormone receptor-negative invasive breast carcinomas. Twelve basal-like carcinomas were selected by immunohistochemistry (lack of ER, PR and HER2 staining and expression of basal cytokeratin 5/6 and/or CK14 and/or EGFR). The comparison series was composed of eleven patients with ER-/PR- and HER2+ tumors.

REANALYSED by: E-GEOD-31519GSE119128

INSTRUMENT(S): [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array

SUBMITTER: Thierry Dubois  

PROVIDER: GSE13787 | GEO | 2008-12-03

SECONDARY ACCESSION(S): PRJNA110619

REPOSITORIES: GEO

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Publications


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.In this study, we focused on the oncogenic phosphatidylinositol 3-kina  ...[more]

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