Faculty Collaboration Database

CXM: a new tool for mapping breast cancer risk in the tumor microenvironment. Cancer Res 2014 Nov 15;74(22):6419-29

Date

08/31/2014

Pubmed ID

25172839

Pubmed Central ID

PMC4247541

DOI

10.1158/0008-5472.CAN-13-3212

Scopus ID

2-s2.0-84918497707 (requires institutional sign-in at Scopus site)   25 Citations

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.

Author List

Flister MJ, Endres BT, Rudemiller N, Sarkis AB, Santarriaga S, Roy I, Lemke A, Geurts AM, Moreno C, Ran S, Tsaih SW, De Pons J, Carlson DF, Tan W, Fahrenkrug SC, Lazarova Z, Lazar J, North PE, LaViolette PS, Dwinell MB, Shull JD, Jacob HJ

Authors

Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Peter LaViolette PhD Professor in the Radiology department at Medical College of Wisconsin
Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

9,10-Dimethyl-1,2-benzanthracene
Animals
Breast Neoplasms
Cell Line, Tumor
Female
Humans
Lymphangiogenesis
Male
Neoplasm Transplantation
Quantitative Trait Loci
Rats
Risk
Transplantation, Heterologous
Tumor Microenvironment