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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2017

01-08-2017 | Preclinical study

Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

Authors: Michael J. Flister, Shirng-Wern Tsaih, Alexander Stoddard, Cody Plasterer, Jaidip Jagtap, Abdul K. Parchur, Gayatri Sharma, Anthony R. Prisco, Angela Lemke, Dana Murphy, Mona Al-Gizawiy, Michael Straza, Sophia Ran, Aron M. Geurts, Melinda R. Dwinell, Andrew S. Greene, Carmen Bergom, Peter S. LaViolette, Amit Joshi

Published in: Breast Cancer Research and Treatment | Issue 1/2017

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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.
Appendix
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Metadata
Title
Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer
Authors
Michael J. Flister
Shirng-Wern Tsaih
Alexander Stoddard
Cody Plasterer
Jaidip Jagtap
Abdul K. Parchur
Gayatri Sharma
Anthony R. Prisco
Angela Lemke
Dana Murphy
Mona Al-Gizawiy
Michael Straza
Sophia Ran
Aron M. Geurts
Melinda R. Dwinell
Andrew S. Greene
Carmen Bergom
Peter S. LaViolette
Amit Joshi
Publication date
01-08-2017
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4311-8

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