@article {199, title = {Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes.}, journal = {Clin Cancer Res}, volume = {19}, year = {2013}, month = {2013 Mar 15}, pages = {1353-62}, abstract = {

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 na{\"\i}ve 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.

}, keywords = {Animals, Breast Neoplasms, Female, Gene Expression Regulation, Neoplastic, Humans, Mammary Neoplasms, Animal, Mice, Radiation, Ionizing, Transcriptome, Tumor Microenvironment, Tumor Suppressor Protein p53}, issn = {1078-0432}, doi = {10.1158/1078-0432.CCR-12-3554}, author = {Nguyen, David H and Fredlund, Erik and Zhao, Wei and Perou, Charles M and Balmain, Allan and Jiang-Hua Mao and Barcellos-Hoff, Mary Helen} }