Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes

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 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 discriminate tumors arising in irradiated hosts. These were applied to publicly available human cancer data sets. 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 TGFβ 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.

Does Microenvironment Contribute to the Etiology of Estrogen Receptor–Negative Breast Cancer?

“…They proposed a biologic "fingerprint" of probable prior exposure to endocrine-disrupting agent. Our preliminary bioinformatics analysis suggests that the gene expression signature derived from host irradiation clusters radiation-preceded cancer in humans (77), consistent with this idea that a microenvironment "meta-profile" could be used to evaluate probable etiology. It is possible that such profiles could identify whether ER-negative breast cancer arises because lifestyle or external events deregulate stem cells or affect the composition of the microenvironment.…”

“…Preliminary bioinformatics analyses show that the genes represented in the irradiated host signature cluster ER-negative human breast cancer and are strongly associated with basal-like and claudin-low molecular profiles (77). Thus, common processes may underlie the prevalence of ER-negative mouse tumors in irradiated hosts and ER-negative sporadic breast cancers most prevalent in young women, AfricanAmerican women, and women irradiated as children.…”

Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53-Null Mammary Carcinomas

“…As found previously in irradiated tissues and tumors arising in g-irradiated mice (30,31), Notch signaling was activated in K18-IHPsi (Fig. 6A).…”

“…In a previous study, we found that gene expression profiles from g-or Si-irradiated mammary gland tissue were comparable in terms of enriching for MaSC signature and implicating NOTCH, TGFb, WNT pathways as upstream regulators (23) up to 12 weeks postirradiation. Tumors arising in hosts irradiated with low doses of sparsely ionizing radiation show a distinct gene expression profile, even though tumors occur many months postirradiation, and even when segregated by ER status (30,31). Because of insufficient number of contemporaneous tumors from g-irradiated host, we were not able to compare the quality difference at the molecular level or control for tumor marker status.…”

“…Notably, the molecular signature of tumors arising in irradiated mice compared with those arising in control mice is informative in human cancer. A host irradiation metaprofile consisting of 353 genes populating modules that represent stem cells, cell motility, macrophages, and autophagy discriminates between tumors arising in sham versus irradiated hosts (31). Human gene orthologs of this murine signature separate cancers arising in previously irradiated patients from sporadic cancers, which suggests that the carcinogenic effect of radiation mediated by the microenvironment is relevant to cancer risk in humans.…”