Document Detail

Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes.
MedLine Citation:
PMID:  23339125     Owner:  NLM     Status:  MEDLINE    
PURPOSE: 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.
EXPERIMENTAL DESIGN: 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.
David H Nguyen; Erik Fredlund; Wei Zhao; Charles M Perou; Allan Balmain; Jian-Hua Mao; Mary Helen Barcellos-Hoff
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-01-21
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  19     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-18     Completed Date:  2013-09-23     Revised Date:  2014-03-26    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1353-62     Citation Subset:  IM    
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MeSH Terms
Breast Neoplasms / etiology,  genetics*,  pathology
Gene Expression Regulation, Neoplastic / radiation effects*
Mammary Neoplasms, Animal / etiology,  genetics*,  pathology
Radiation, Ionizing
Transcriptome / radiation effects
Tumor Microenvironment / genetics,  radiation effects
Tumor Suppressor Protein p53 / genetics*,  metabolism
Grant Support
P50 CA058223/CA/NCI NIH HHS; P50-CA58223/CA/NCI NIH HHS; R01 CA101227/CA/NCI NIH HHS; R01-CA138255/CA/NCI NIH HHS; R01-CA148761/CA/NCI NIH HHS
Reg. No./Substance:
0/Tumor Suppressor Protein p53

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