title: Extensive rewiring of epithelial-stromal co-expression networks in breast cancer.
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.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. eoh1@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. eoh1@bidmc.harvard.edu.|Harvard Medical School, Boston, MA, 02215, USA. eoh1@bidmc.harvard.edu.
authors.forename: Eun-Yeong
authors.initials: EY
authors.lastname: Oh
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. djscristo@gmail.com.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. djscristo@gmail.com.|Harvard Medical School, Boston, MA, 02215, USA. djscristo@gmail.com.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Christensen
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. sghanta2@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. sghanta2@bidmc.harvard.edu.|Harvard Medical School, Boston, MA, 02215, USA. sghanta2@bidmc.harvard.edu.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Ghanta
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. jjeong1@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. jjeong1@bidmc.harvard.edu.|Harvard Medical School, Boston, MA, 02215, USA. jjeong1@bidmc.harvard.edu.
authors.forename: Jong Cheol
authors.initials: JC
authors.lastname: Jeong
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. obucur@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. obucur@bidmc.harvard.edu.|Harvard Medical School, Boston, MA, 02215, USA. obucur@bidmc.harvard.edu.
authors.forename: Octavian
authors.initials: O
authors.lastname: Bucur
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. bglass@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. bglass@bidmc.harvard.edu.|Harvard Medical School, Boston, MA, 02215, USA. bglass@bidmc.harvard.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glass
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. lmontase@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. lmontase@bidmc.harvard.edu.|Harvard Medical School, Boston, MA, 02215, USA. lmontase@bidmc.harvard.edu.
authors.forename: Laleh
authors.initials: L
authors.lastname: Montaser-Kouhsari
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. nwknoblauch@gmail.com.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. nwknoblauch@gmail.com.|Harvard Medical School, Boston, MA, 02215, USA. nwknoblauch@gmail.com.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Knoblauch
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada. nicholas.bertos@mcgill.ca.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bertos
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada. sadiq.saleh@gmail.com.
authors.forename: Sadiq Mi
authors.initials: SM
authors.lastname: Saleh
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. bhaibeka@uhnresearch.ca.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada. bhaibeka@uhnresearch.ca.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada. morag.park@mcgill.ca.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. abeck2@bidmc.harvard.edu.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. abeck2@bidmc.harvard.edu.|Harvard Medical School, Boston, MA, 02215, USA. abeck2@bidmc.harvard.edu.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
mesh_terms: D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D011960:Receptors, Estrogen; D017154:Stromal Cells / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D011960:Receptors, Estrogen