title: Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ.
abstract: BACKGROUND
  Basal-like and luminal breast cancers have distinct stromal-epithelial interactions, which play a role in progression to invasive cancer. However, little is known about how stromal-epithelial interactions evolve in benign and pre-invasive lesions.
  
  
  METHODS
  To study epithelial-stromal interactions in basal-like breast cancer progression, we cocultured reduction mammoplasty fibroblasts with the isogenic MCF10 series of cell lines (representing benign/normal, atypical hyperplasia, and ductal carcinoma in situ). We used gene expression microarrays to identify pathways induced by coculture in premalignant cells (MCF10DCIS) compared with normal and benign cells (MCF10A and MCF10AT1). Relevant pathways were then evaluated in vivo for associations with basal-like subtype and were targeted in vitro to evaluate effects on morphogenesis.
  
  
  RESULTS
  Our results show that premalignant MCF10DCIS cells express characteristic gene expression patterns of invasive basal-like microenvironments. Furthermore, while hepatocyte growth factor (HGF) secretion is upregulated (relative to normal, MCF10A levels) when fibroblasts are cocultured with either atypical (MCF10AT1) or premalignant (MCF10DCIS) cells, only MCF10DCIS cells upregulated the HGF receptor MET. In three-dimensional cultures, upregulation of HGF/MET in MCF10DCIS cells induced morphological changes suggestive of invasive potential, and these changes were reversed by antibody-based blocking of HGF signaling. These results are relevant to in vivo progression because high expression of a novel MCF10DCIS-derived HGF signature was correlated with the basallike subtype, with approximately 86% of basal-like cancers highly expressing the HGF signature, and because high expression of HGF signature was associated with poor survival.
  
  
  CONCLUSIONS
  Coordinated and complementary changes in HGF/MET expression occur in epithelium and stroma during progression of pre-invasive basal-like lesions. These results suggest that targeting stroma-derived HGF signaling in early carcinogenesis may block progression of basal-like precursor lesions.
authors.forename: Patricia
authors.initials: P
authors.lastname: Casbas-Hernandez
authors.forename: Monica
authors.initials: M
authors.lastname: D'Arcy
authors.forename: Erick
authors.initials: E
authors.lastname: Roman-Perez
authors.forename: Heather Ann
authors.initials: HA
authors.lastname: Brauer
authors.forename: Kirk
authors.initials: K
authors.lastname: McNaughton
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Miller
authors.forename: Raghav K
authors.initials: RK
authors.lastname: Chhetri
authors.forename: Amy L
authors.initials: AL
authors.lastname: Oldenburg
authors.forename: Jodie M
authors.initials: JM
authors.lastname: Fleming
authors.forename: Keith D
authors.initials: KD
authors.lastname: Amos
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016000:Cluster Analysis; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D017154:Stromal Cells / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D016207:Cytokines; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
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