Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer.

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 SSIL2R? and SS.BN3IL2R? CXM strains. RESULTS:Breast cancer xenografts implanted in SS.BN3IL2R? (consomic) had significant tumor growth inhibition compared with SSIL2R? (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2R? tumors. We hypothesized that decreased growth of SS.BN3IL2R? tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2R? and SS.BN3IL2R? 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.BN3IL2R? tumors compared with SSIL2R?. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2R? 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.

SUBMITTER: Flister MJ 

PROVIDER: S-EPMC6404538 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature