Unknown,Transcriptomics,Genomics,Proteomics

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Expression of Epithelial-to-Mesenchymal Transition (EMT)-associated genes in extratumoral microenvironment predicts poor clinical outcome in breast cancer patients

ABSTRACT: Introduction: A gene expression signature indicative of active wound responses is common to more than 90% of non-neoplastic tissues adjacent to breast cancer, but these tissues also show substantial heterogeneity, suggesting different microenvironmental subtypes. Genomic variation in the extratumoral microenvironment has received limited study. Methods: Gene expression analysis from 72 patient-derived samples adjacent to invasive breast cancer or ductal carcinoma in situ was evaluated. Unsupervised clustering identified two distinct gene expression subgroups that differed substantially in expression of genes associated with epithelial-to-mesenchymal transition (EMT). We evaluated the prognostic and biological relevance of this extratumoral EMT-like signature using clinical and experimental approaches. Results: We found that the extratumoral EMT-like signature was not significantly associated with overall survival among all patients [Hazard Ratio (HR) = 1.4, 95% CI 0.6 - 2.8, p=0.337], but there was a strong association with overall survival among estrogen receptor (ER)-positive patients [HR = 2.5, 95% CI 0.9 – 6.7, p=0.062] or hormone-treated patients [HR=2.6, 95% CI 1.0 – 7.0, p=0.045]. In addition, co-culturing of ER-positive MCF-7 cells with cells undergoing EMT increased migration of MCF7 cells in a TGF-β1 dependent manner. Conclusion: Together, these results suggest that the presence of an EMT-like signature in the cancer-adjacent extratumoral microenvironment may influence the aggressiveness of the ER-positive tumors and that ER-positive patients with these extratumoral signatures may require additional treatments or more aggressive surgeries. Reference vs. test sample. 74 test samples (12 breast tumors, 62 normal tissue adjacent to breast tumor) from 72 patients.

ORGANISM(S): Homo sapiens

SUBMITTER: Melissa Troester

PROVIDER: E-GEOD-31589 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets. Comparison of reference samples against treatment

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Expression of Epithelial-to-Mesenchymal Transition (EMT)-associated genes in extratumoral microenvironment predicts poor clinical outcome in breast cancer patients

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