CXM: A new tool for mapping breast cancer risk in the tumor microenvironment

Michael J. Flister, Bradley T. Endres, Nathan Rudemiller, Allison B. Sarkis, Stephanie Santarriaga, Ishan Roy, Angela Lemke, Aron M. Geurts, Carol Moreno, Sophia Ran, Shirng Wern Tsaih, Jeffery De Pons, Daniel F. Carlson, Wenfang Tan, Scott C. Fahrenkrug, Zelmira Lazarova, Jozef Lazar, Paula E. North, Peter S. LaViolette, Michael B. DwinellJames D. Shull, Howard J. Jacob*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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 g consomic model compared with the SS 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 g 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.

Original languageEnglish (US)
Pages (from-to)6419-6429
Number of pages11
JournalCancer Research
Issue number22
StatePublished - Nov 15 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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