Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes

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 naive hosts. 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 TGFB levels showed that inflammation was robustly associated with claudin-low tumors. 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. Total RNA was extracted from mammary tumors derived from transplantations of non-irradiated p53null mammary fragments into irradiated hosts. We analyized a total of 32 p53null tumors from irradiated wild type mice: 9 from sham-irradiated hosts, and 23 from irradiated hosts. We also analyzed 24 tumors from irradiated TGFb1 heterozygote hosts: 6 from sham-irradiated hosts, and 18 from irradiated hosts.