Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer
PurposeMultiple 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.MethodsTo 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 SSIL2Rg and SS.BN3IL2Rg CXM strains.ResultsBreast cancer xenografts implanted in SS.BN3IL2Rg (consomic) had significant tumor growth inhibition compared with SSIL2Rg (parental control) despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rg tumors. We hypothesized that decreased growth of SS.BN3IL2Rg tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rg and SS.BN3IL2Rg 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.BN3IL2Rg tumors compared with SSIL2Rg. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rg 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.ConclusionsCollectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.
Breast Cancer Research and Treatment