title: High Intratumoral Stromal Content Defines Reactive Breast Cancer as a Low-risk Breast Cancer Subtype.
abstract: OBJECTIVE
  The current study evaluated associative effects of breast cancer cells with the tumor microenvironment and its influence on tumor behavior.
  
  
  METHODS
  Formalin-fixed, paraffin-embedded tissue and matched protein lysates were evaluated from two independent breast cancer patient datasets (TCGA and MD Anderson). Reverse-phase protein arrays (RPPA) were utilized to create a proteomics signature to define breast tumor subtypes. Expression patterns of cell lines and normal breast tissues were utilized to determine markers that were differentially expressed in stroma and cancer cells. Protein localization and stromal contents were evaluated for matched cases by imaging.
  
  
  RESULTS
  A subtype of breast cancers designated "Reactive," previously identified by RPPA that was not predicted by mRNA profiling, was extensively characterized. These tumors were primarily estrogen receptor (ER)-positive/human EGF receptor (HER)2-negative, low-risk cancers as determined by enrichment of low-grade nuclei, lobular or tubular histopathology, and the luminal A subtype by PAM50. Reactive breast cancers contained high numbers of stromal cells and the highest extracellular matrix content typically without infiltration of immune cells. For ER-positive/HER2-negative cancers, the Reactive classification predicted favorable clinical outcomes in the TCGA cohort (HR, 0.36; P < 0.05).
  
  
  CONCLUSIONS
  A protein stromal signature in breast cancers is associated with a highly differentiated phenotype. The stromal compartment content and proteins are an extended phenotype not predicted by mRNA expression that could be utilized to subclassify ER-positive/HER2-negative breast cancers. Clin Cancer Res; 22(20); 5068-78. ©2016 AACR.
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Dennison
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maria
authors.initials: M
authors.lastname: Shahmoradgoli
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.affiliation: Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Alana
authors.initials: A
authors.lastname: Welm
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sikora
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. gmills@mdanderson.org.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000145:classification* / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D012334:RNA, Neoplasm / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human