title: Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes.
abstract: OBJECTIVE
  Ionizing radiation is a well-established carcinogen in rodent models and a risk factor associated with human cancer. We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53-null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in naïve hosts. We asked whether expression metaprofiles could discern radiation-preceded human cancer or be informative in sporadic breast cancers.
  
  
  METHODS
  Affymetrix microarray gene expression data from 56 Trp53-null mammary tumors were used to define gene profiles and a centroid that discriminates tumors arising in irradiated hosts. These were applied to publicly available human cancer datasets.
  
  
  RESULTS
  Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages, and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation-preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor-negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGF-β levels showed that inflammation was robustly associated with claudin-low tumors.
  
  
  CONCLUSIONS
  Detection of radiation-preceded human cancer by the irradiated host metaprofile raises possibilities of assessing human cancer etiology. Moreover, the association of the irradiated host metaprofiles with estrogen receptor-negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers.
authors: Department of Radiation Oncology, New York University School of Medicine, New York, New York 10016, USA.
authors: David H
authors: DH
authors: Nguyen
authors: Erik
authors: E
authors: Fredlund
authors: Wei
authors: W
authors: Zhao
authors: Charles M
authors: CM
authors: Perou
authors: Allan
authors: A
authors: Balmain
authors: Jian-Hua
authors: JH
authors: Mao
authors: Mary Helen
authors: MH
authors: Barcellos-Hoff
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D011839:Radiation, Ionizing; D059467:Transcriptome / Q000528:radiation effects; D059016:Tumor Microenvironment / Q000235:genetics / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53