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Expanded Materials and Methods, Supplemental Figures, and Supplemental Tables Figure S1. Flow cytometric analysis of peripheral blood from SS, SS.BN3, SSIL2Rγ, and SS.BN3IL2Rγ rats. Figure S2.SH2B3 specifically marks CD31+ blood vessels, but not LYVE1+ lymphatic vessels. Table S1. Peripheral blood analysis of SS, SS.BN3, SSIL2Rγ and SS.BN3IL2Rγ rats. Table S2. Genes located in the overlapping portions of the rat chromosome 3 cancer QTLs. Table S3. Variants that cosegregate between tumor resistant (BN and Cop) and tumor susceptible (ACI, F344, and SS) rat strains.

The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous, and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that affect only the tumor microenvironment. In CXM, human breast cancer cells are orthotopically implanted into immunodeficient consomic strains and tumor metrics are quantified (e.g., growth, vasculogenesis, and metastasis). Because the strain backgrounds vary, whereas the malignant tumor cells do not, any observed changes in tumor progression are due to genetic differences in the nonmalignant microenvironment. Using CXM, we defined genetic variants on rat chromosome 3 that reduced relative tumor growth and hematogenous metastasis in the SS.BN3IL2Rγ consomic model compared with the SSIL2Rγ parental strain. Paradoxically, these effects occurred despite an increase in the density of tumor-associated blood vessels. In contrast, lymphatic vasculature and lymphogenous metastasis were unaffected by the SS.BN3IL2Rγ background. Through comparative mapping and whole-genome sequence analysis, we narrowed candidate variants on rat chromosome 3 to six genes with a priority for future analysis. Collectively, our results establish the utility of CXM to localize genetic variants affecting the tumor microenvironment that underlie differences in breast cancer risk. Cancer Res; 74(22); 6419–29. ©2014 AACR.