Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes

Radiation Oncology, New York University School of Medicine.
Clinical Cancer Research (Impact Factor: 8.72). 01/2013; 19(6). DOI: 10.1158/1078-0432.CCR-12-3554
Source: PubMed


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.

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.

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.

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Available from: Mary Helen Barcellos-Hoff, Jan 24, 2014
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    • "Similar characterizations have not yet been reported for solid tumors (with the exception of minimal data on mammary cancer Imaoka et al., 2007; Illa-Bochaca et al., 2014a), but may reveal radiation signatures or even radiation quality signatures. For example the gene expression profile of Trp53 null mammary tumors arising in irradiated mice compared to controls can cluster not only human breast cancers into prognostic subtypes but can also cluster radiation-preceded from spontaneous human thyroid cancers and sarcomas (Nguyen et al., 2013). Such signatures could have profound implications on human radiation epidemiology studies because they may be used to distinguish radiogenic tumors from spontaneous tumors of the same histology. "
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