title: CXM: a new tool for mapping breast cancer risk in the tumor microenvironment.
abstract: 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.BN3(IL2Rγ) consomic model compared with the SS(IL2Rγ) 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.BN3(IL2Rγ) 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.
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin. jacob@mcw.edu mflister@mcw.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Flister
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Endres
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Nathan
authors.initials: N
authors.lastname: Rudemiller
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Allison B
authors.initials: AB
authors.lastname: Sarkis
authors.affiliation: Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Santarriaga
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ishan
authors.initials: I
authors.lastname: Roy
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Angela
authors.initials: A
authors.lastname: Lemke
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Carol
authors.initials: C
authors.lastname: Moreno
authors.affiliation: SimonsCooper Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois. Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Sophia
authors.initials: S
authors.lastname: Ran
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Shirng-Wern
authors.initials: SW
authors.lastname: Tsaih
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Jeffery
authors.initials: J
authors.lastname: De Pons
authors.affiliation: Recombinetics Inc, Saint Paul, Minnesota.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Carlson
authors.affiliation: Department of Animal Science, University of Minnesota, Saint Paul, Minnesota. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Tan
authors.affiliation: Recombinetics Inc, Saint Paul, Minnesota. Department of Animal Science, University of Minnesota, Saint Paul, Minnesota. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Fahrenkrug
authors.affiliation: Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Zelmira
authors.initials: Z
authors.lastname: Lazarova
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Paula E
authors.initials: PE
authors.lastname: North
authors.affiliation: Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Peter S
authors.initials: PS
authors.lastname: LaViolette
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin. Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin. UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors.forename: James D
authors.initials: JD
authors.lastname: Shull
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin. jacob@mcw.edu mflister@mcw.edu.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis; D008297:Male; D009368:Neoplasm Transplantation; D040641:Quantitative Trait Loci; D051381:Rats; D012306:Risk; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene