Faculty Collaboration Database

Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer. Breast Cancer Res Treat 2017 Aug;165(1):53-64

Date

06/02/2017

Pubmed ID

28567545

Pubmed Central ID

PMC6404538

DOI

10.1007/s10549-017-4311-8

Scopus ID

2-s2.0-85020059895 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

PURPOSE: Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function.

METHODS: To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the genetic backgrounds of the xenograft host strains differ, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME-specific modifier(s) on the substituted chromosome (consomic) or subchromosomal region (congenic). Here, we assessed TME modifiers of growth, angiogenesis, and vascular function of tumors implanted in the SS^IL2Rγ and SS.BN3^IL2Rγ CXM strains.

RESULTS: Breast cancer xenografts implanted in SS.BN3^IL2Rγ (consomic) had significant tumor growth inhibition compared with SS^IL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3^IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3^IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SS^IL2Rγ and SS.BN3^IL2Rγ tumor vascular function was examined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analysis of primary blood endothelial cells, all of which revealed altered vascular function in SS.BN3^IL2Rγ tumors compared with SS^IL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3^IL2Rγ tumors, among which DLL4 was differentially expressed and co-localized to a host TME modifier locus (Chr3: 95-131 Mb) that was identified by congenic mapping.

CONCLUSIONS: Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.

Author List

Flister MJ, Tsaih SW, Stoddard A, Plasterer C, Jagtap J, Parchur AK, Sharma G, Prisco AR, Lemke A, Murphy D, Al-Gizawiy M, Straza M, Ran S, Geurts AM, Dwinell MR, Greene AS, Bergom C, LaViolette PS, Joshi A

Authors

Mona Al-Gizawiy PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
Melinda R. Dwinell PhD Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Amit Joshi PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Peter LaViolette PhD Professor in the Radiology department at Medical College of Wisconsin
Michael W. Straza MD, PhD Assistant Professor in the Radiation Oncology 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

Adaptor Proteins, Signal Transducing
Animals
Animals, Congenic
Calcium-Binding Proteins
Cell Line, Tumor
Cell Proliferation
Endothelial Cells
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Genetic Predisposition to Disease
Heterografts
Humans
Intercellular Signaling Peptides and Proteins
Magnetic Resonance Imaging
Neovascularization, Pathologic
Phenotype
Rats
Signal Transduction
Time Factors
Triple Negative Breast Neoplasms
Tumor Burden
Tumor Microenvironment
X-Ray Microtomography