Breast cancer is the most prevalent female malignancy and is highly heritable, yet the majority of breast cancer risk remains undefined. Heritable factors underlie most aspects of breast cancer risk [e.g., incidence, age-of- onset, metastatic progression, and disease-free survival]. In addition to variants that impact tumor cells directly (i.e., tumorigenicity), heritability is implicated in multiple components of the tumor microenvironment [e.g., tissue remodeling, angiogenesis, and immunity], which also impact tumorigenesis and progression. However, the genetic variant(s) underlying differences in the tumor microenvironment have rarely been the focus of genetic mapping studies and as such, remain poorly defined. Our goal is to develop a new genetic model to assess breast cancer risk in the tumor microenvironment. We have developed a new model of breast cancer (termed the Consomic Xenograft Model - CXM) that focuses on genetic mapping of strain-specific variant(s) that impact tumor progression through the tumor microenvironment. A consomic rat is one in which an entire chromosome is introgressed into the isogenic background of another inbred strain by selective breeding. Thus, observed phenotypes can be linked to single chromosomes and then further elucidated by comparative sequence analysis and/or selective backcrossing to yield smaller congenics. In CXM, the consomic and parental strains are converted to SCID (severe combined immunodeficiency), so that orthotopically xenografted human breast cancer cells can be tested in vivo. Because the human breast cancer cells are not varied between strains, any differences in breast cancer progression (e.g., primary site growth, vasculogenesis, and distal metastasis) are due solely to genetic differences in the tumor microenvironment, not the malignant cancer cells. CXM utilizes transgenically tagged human cancer cells with defined properties (e.g., triple-negative, pro-metastatic, etc.). Thus, it enables testing of clinically relevant cancer models in strain backgrounds with varying genetic predispositions to breast cancer. Using CXM, we found that BN-derived genetic variant(s) on rat chromosome 3 significantly suppress tumor growth and hematogenous metastasis, whereas lymphatic vasculature and lymphogenous metastasis were completely unaffected. We hypothesize that decreased tumor growth and hematogenous metastasis are due to alterations in the tumor blood vasculature caused by the genetic variant(s) on BN rat chromosome 3. To test this hypothesis and elucidate the genetic mechanism(s), we propose to (1) narrow the causative gene(s) and characterize the underlying mechanism(s) that inhibit breast cancer progression using CXM analysis of two breast cancer cell lines; (2) identify the blood vessel-specific genetic and molecular mechanism(s) that alter tumor blood vasculature and hematogenous metastasis in the SSBN3IL2R? consomic rat; and (3) test the role of the WISP2/WNT signaling pathway in decreased breast cancer risk in the SSBN3IL2R? consomic rat. These studies will provide mechanistic insight to the role of the tumor microenvironment in breast cancer risk.
Breast cancer is highly heritable, yet the majority of causative risk variants remain unknown. Of the characterized risk variants, most are tumor cell-autonomous, with far less emphasis placed on germline variants that might impact risk through the tumor microenvironment. In this study we develop and utilize a novel tool (Consomic Xenograft Model) for elucidating germline variants that impact breast cancer risk through the tumor microenvironment.
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