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Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer. Breast Cancer Res Treat 2017 Aug;165(1):53-64 PMID: 28567545

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 SSIL2Rγ and SS.BN3IL2Rγ CXM strains.

RESULTS: Breast cancer xenografts implanted in SS.BN3IL2Rγ (consomic) had significant tumor growth inhibition compared with SSIL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rγ and SS.BN3IL2Rγ 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.BN3IL2Rγ tumors compared with SSIL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rγ 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

Carmen R. Bergom MD, PhD Assistant Professor in the Radiation Oncology department at Medical College of Wisconsin
Melinda R. Dwinell PhD Center Associate Director, Associate Professor in the Physiology department at Medical College of Wisconsin
Michael J. Flister PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Andrew S. Greene PhD Interim Vice Chair, Chief, Professor in the Biomedical Engineering department at Medical College of Wisconsin
Amit Joshi PhD Associate Professor in the Biomedical Engineering department at Medical College of Wisconsin
Peter LaViolette PhD Assistant Professor in the Radiology department at Medical College of Wisconsin
Michael W. Straza MD, PhD Instructor in the Radiation Oncology department at Medical College of Wisconsin



View this publication's entry at the Pubmed website PMID: 28567545
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