Abstract
Background: 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. Results: 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. Conclusions: 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.
Original language | English |
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Article number | 128 |
Journal | Genome Biology |
Volume | 16 |
Issue number | 1 |
DOIs | |
State | Published - Jun 19 2015 |
Bibliographical note
Publisher Copyright:© 2015 Oh et al.
Funding
This work was supported by funding from the Klarman Family Foundation, Susan G. Komen for the Cure Foundation under Award Number CCR14302670, the National Cancer Institute of the National Institutes of Health (SPORE grant P50CA168504 Career Development Award), the National Library Of Medicine of the National Institutes of Health under Award Number K22LM011931 (to AHB), and the Canadian Natural Sciences and Engineering Research Council (RGPIN-2015-03654 to BHK). Generation of the dataset from McGill University was supported by funding from the Database and Tissue Bank Axis of the Réseau de Recherche en Cancer of the Fonds de Recherche du Québec-Santé and the Québec Breast Cancer Foundation (to MP). The funders had no role in the design, collection, analysis, interpretation of data, writing of the manuscript, or the decision to submit the manuscript for publication.
Funders | Funder number |
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National Library of Medicine of the National Institutes of Health | K22LM011931 |
Susan G. Komen for the Cure Foundation | CCR14302670 |
National Institutes of Health (NIH) | |
National Childhood Cancer Registry – National Cancer Institute | P50CA168504 |
National Childhood Cancer Registry – National Cancer Institute | |
Klarman Family Foundation | |
McGill University | |
Fondation du cancer du sein du Québec | |
Natural Sciences and Engineering Research Council of Canada | RGPIN-2015-03654 |
Natural Sciences and Engineering Research Council of Canada |
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Genetics
- Cell Biology