Unknown,Transcriptomics,Genomics,Proteomics

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Transfer of clinically relevant gene expression signatures in breast cancer: from Affymetrix microarray to Illumina RNA-Sequencing technology

ABSTRACT: Microarrays have revolutionized breast cancer (BC) research by enabling studies of gene expression on a transcriptome-wide scale. Recently, RNA-Sequencing (RNA-Seq) has emerged as an alternative for precise readouts of the transcriptome. To date, no study has compared the ability of the two technologies to quantify clinically relevant individual genes and microarray-derived gene expression signatures (GES) in a set of BC samples encompassing the known molecular BC's subtypes. To accomplish this, the RNA from 57 BCs representing the four main molecular subtypes (triple negative, HER2 positive, luminal A, luminal B), was profiled with Affymetrix HG-U133 Plus 2.0 chips and sequenced using the Illumina HiSeq 2000 platform. The correlations of three clinically relevant BC genes, six molecular subtype classifiers, and a selection of 21 GES were evaluated. 58 tumors representing the different molecular subtypes [triple negative (ER-/PgR-/HER2-); HER2 positive (HER2+); luminal A (ER+/HER2-/histological grade 1), luminal B (ER+/HER2-/histological grade 3)] were obtained from patients recruited between 2007 and 2011 at the Institut Jules Bordet. RNA was profiled using the Affymetrix HG-U133 Plus 2.0 chips and sequenced on the Illumina platform, producing ~30 million 50 bp paired-end reads per sample. The reads alignment and expression quantification were performed using the Tophat/Cufflinks pipeline and the Ensembl genome version hg19. The Affymetrix microarray data were normalized using fRMA and probesets were selected based on the JetSet reannotation package. This submission represents the gene expression component of the study only.

ORGANISM(S): Homo sapiens

SUBMITTER: David Brown

PROVIDER: E-GEOD-43358 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1-3. Pik3ca and p53 are the two most frequently mutated genes and are associated with different types of human breast cancers4. The cellular origin and the mechanisms leading to Pik3ca-induced tumour heterogeneity remain unknown. Here, we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and its impact on tumour heterogeneity. Surprisingly, oncogenic Pik3ca-H1047R expression at physiological levels5 in basal cells (BCs) using K5CREERT2 induced the formation of luminal ER+PR+ tumours, while its expression in luminal cells (LCs) using K8CREERT2 gave rise to luminal ER+PR+ tumours or basal-like ER-PR- tumours. Concomitant deletion of p53 and expression of Pik3ca-H1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca-H1047R in unipotent BCs gave rise to luminal-like cells, while its expression in unipotent LCs gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that have undergone cell fate transition upon Pik3ca-H1047R expression in unipotent progenitors demonstrate a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures, characteristic of the different cell fate switches that occur upon Pik3ca-H1047R expression in BC and LCs, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca-H1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation. Luminal and basal cells, or tumour cells, from mice in which expression of PIK3CA-H1047R and YFP (and in some conditions loss of p53) was targeted in basal cells using K5CREERT2 or in luminal cells using K8CREERT2 were FACS isolated and RNA was extracted before being hybridized Affymetrix microarrays.

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Transfer of clinically relevant gene expression signatures in breast cancer: from Affymetrix microarray to Illumina RNA-Sequencing technology

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