Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

• Published in: Breast cancer research and treatment 2017-08, Vol.165 (1), p.53-64
• Main Authors: Flister, Michael J., Tsaih, Shirng-Wern, Stoddard, Alexander, Plasterer, Cody, Jagtap, Jaidip, Parchur, Abdul K., Sharma, Gayatri, Prisco, Anthony R., Lemke, Angela, Murphy, Dana, Al-Gizawiy, Mona, Straza, Michael, Ran, Sophia, Geurts, Aron M., Dwinell, Melinda R., Greene, Andrew S., Bergom, Carmen, LaViolette, Peter S., Joshi, Amit
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Angiogenesis; Animals; Animals, Congenic; Blood vessels; Breast cancer; Calcium-Binding Proteins; Cancer research; CAT scans; Cell Line, Tumor; Cell Proliferation; Computed tomography; Disease susceptibility; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Gene expression; Gene Expression Regulation, Neoplastic; Gene mapping; Gene Regulatory Networks; Genetic aspects; Genetic engineering; Genetic Predisposition to Disease; Genetically modified organisms; Heterografts; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Magnetic Resonance Imaging; Medicine; Medicine & Public Health; Neovascularization, Pathologic; NMR; Nuclear magnetic resonance; Oncology; Phenotype; Phenotypic variations; Preclinical Study; Rats; Signal Transduction; Time Factors; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Burden; Tumor cells; Tumor Microenvironment; Tumors; X-Ray Microtomography; Xenografts
• ISSN: 0167-6806; 1573-7217; 1573-7217
• DOI: 10.1007/s10549-017-4311-8

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.