Unknown,Transcriptomics,Genomics,Proteomics

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Molecular Characterization of the Vasculature of Patients with Infiltrating Ductal Carcinoma generates a Gene Signature predictive of Breast Cancer Survival

ABSTRACT: Introduction: Targeting of the tumor vasculature has evolved into an integral part of existing standard anti-cancer therapies. However, recent pre-clinical and clinical studies have shown that the efficacy of these treatments is temporary at most and frequently followed by the renewed tumor growth, indicating that these targets may not be robust. Methods: We transcriptionally profiled laser capture microdissection isolated microvessels from tumor and matching adjacent normal tissue samples obtained from breast cancer patients diagnosed with infiltrating ductal carcinoma. Gene expression profiles were generated and analyzed using Genespring and the web-based WebGestalt bioinformatics Toolkit. Several differentially expressed genes were validated by immunohistochemistry. To further mine our data set we used a novel integrative systems biology network approach to identify a gene signature that could robustly stratify breast cancer patient populations. Results: Vascular enrichment of the LCM samples was confirmed by Q-PCR of CD31. Hierarchical two-dimensional clustering of the transcriptome data identified 219 significantly upregulated transcripts in at least 4/8 patient samples (cut-off >1.3-fold, p<0.05). Several genes AGRN, FLNA and ILR4 were selected and their protein overexpression was confirmed in the tumor tissue. Additional mining of the data set using the clinical information associated with these tissues by applying an integrative bioinformatics network method generated a 15-gene M-bM-^@M-^XVascular-Derived Prognostic PredictorM-bM-^@M-^Y that is able to stratify patient populations in to high- and low- risk groups. Conclusions: The overall heterogeneity observed in the vascular gene expression patterns in the infiltrating ductal carcinoma samples poses a significant problem for these individual genes to be used as a robust vascular breast cancer specific marker or therapeutic target. Using an integrative bioinformatics network approach allowed us to identify a 15-gene M-bM-^@M-^XVascular-Derived Prognostic PredictorM-bM-^@M-^Y that can robustly identify patients with an increased risk of local recurrence. Stratifying patient populations using this gene signature may lead to better patient-tailored treatment regimes. Two-color microarrays comparing laser-captured microvessels from the tumors and matching adjacent normal tissues of 8 breast cancer patients

ORGANISM(S): Homo sapiens

SUBMITTER: Andre Nantel

PROVIDER: E-GEOD-43379 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Purpose: In all vertebrates, the thymus is necessary and sufficient for production of classic adaptive T cells. The key components of the thymus are cortical and medullary thymic epithelial cells (cTECs and mTECs). Despite the capital role of TECs, our understanding of TEC biology is quite rudimentary. For instance, we ignore what might be the extent of divergence in the functional program of these two TECs populations. It also remains unclear why the number of TECs decreases rapidly with age, thereby leading to progressive thymic insufficiency. Methods: Systems level understanding of cell function begins with gene expression profiling, and the transcriptome is currently the only '-ome' that can be reliably tackled in its entirety in freshly harvested primary cells. In order to gain novel insights into TEC biology, we therefore decided to analyse the whole transcriptome of cTECs, mTECs and skin epithelial cells. We elected to analyse gene expression using RNA-seq rather microarrays because RNA-seq has higher sensitivity and dynamic range coupled to lower technical variations. Results: Our deep sequencing approach provides a unique perspective into the transcriptome of TECs. Consistent with their ability to express ectopic genes, we found that mTECs expressed more genes than other cell populations. Out of a total of 15,069 genes expressed in TECs, 25% were differentially expressed by at least 5-fold in cTECs vs. mTECs. Genes expressed at higher levels in cTECs than mTECs regulate numerous cell functions including cell differentiation, cell movement and microtubule dynamics. Almost all positive regulators of the cell cycle were overexpressed in skin ECs relative to TECs. Conclusions: Our RNA-seq data provide novel insights into the transcriptional landscape of TECs, highlight substantial divergences in the transcriptome of TEC subsets and suggest that cell cycle progression is differentially regulated in TECS and skinECs. We believe that our work will therefore represent a valuable resource and will be of great interest to readers working in biological sciences, particularly in the areas of immunology and systems biology. The mRNA profiles of cTEC, mTEC (from 14 thymi of 7-days old C57BL/6 mice) and skinEC (from the trunk and dorsum of seven newborn mice) were generated by RNA-sequencing using Illumina HiSeq2000.

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Molecular Characterization of the Vasculature of Patients with Infiltrating Ductal Carcinoma generates a Gene Signature predictive of Breast Cancer Survival

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