Extensive rewiring of epithelial-stromal co-expression networks in breast cancer

Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. We develop a framework for building genome-wide epithelial-stromal co-expression networks com...

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Bibliographic Details
Published in:Genome Biology 2015-06, Vol.16 (1), p.128, Article 128
Main Authors: Oh, Eun-Yeong, Christensen, Stephen M, Ghanta, Sindhu, Jeong, Jong Cheol, Bucur, Octavian, Glass, Benjamin, Montaser-Kouhsari, Laleh, Knoblauch, Nicholas W, Bertos, Nicholas, Saleh, Sadiq Mi, Haibe-Kains, Benjamin, Park, Morag, Beck, Andrew H
Format: Article
Language:English
Subjects:
Bioinformatics
Breast - metabolism
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Carcinogenesis
Computer applications
Connectivity
Data processing
Datasets
Epithelial Cells - metabolism
Epithelium
Female
Fibroblasts
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Genomes
Genomics
Humans
Image processing
Immunohistochemistry
Invasiveness
Lasers
Network hubs
Protein expression
Proteins
Receptors, Estrogen
Stroma
Stromal Cells - metabolism
Tissue Array Analysis
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Summary:Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive rewiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, and estrogen receptor-positive and estrogen receptor-negative invasive breast cancer, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in invasive breast cancer mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially localized transcriptomic data. The analysis provides new biological insights into the rewiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer.
ISSN:1474-760X
1474-7596
1465-6906
1474-760X
1465-6914
DOI:10.1186/s13059-015-0675-4