Abstract 782: Revisiting the angiogenic switch: Host genetic modifiers induce non-productive angiogenesis and inhibit breast cancer

Abstract

Abstract Purpose: Multiple aspects of the tumor microenvironment (TME) impact breast cancer risk, 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/congenic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the host strain backgrounds are different, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME modifier(s) on the substituted chromosome (i.e., consomic) or subchromosomal region (i.e., congenic) of the host’s germline DNA. Here, we assessed TME modifiers on rat chromosome 3 (RNO3) that impact growth, angiogenesis, vascular function, and hematogenous metastasis of tumors implanted in the SSIL2Rγ and SS.BN3IL2Rγ CXM strains. Results: Breast cancer xenografts implanted in SS.BN3IL2Rγ (consomic) had significant inhibition of tumor growth and hematogenous metastasis 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 revealed a dysregulated vascular signaling network in SS.BN3IL2Rγ tumors, among which DLL4 was localized to RNO3 and downregulated on the vasculature of SS.BN3IL2Rγ tumors compared with SSIL2Rγ. CXM congenic mapping confirmed that the DLL4 modifier allele is physically linked with breast cancer inhibition by inducing non-productive angiogenesis. Finally, using whole genome sequencing of the germline DNA, we have identified multiple polymorphisms in the DLL4 promoter and a proximal regulatory lncRNA that likely alter DLL4 expression and function. Conclusions: Collectively, these data suggest that DLL4 can function as a heritable modifier of non-productive angiogenesis that inhibits breast cancer growth and metastasis. Citation Format: Michael Flister, Cody Plasterer, Shirng-Wern Tsaih, Angela Lemke, Dana Murphy, Amit Joshi, Peter LaViolette, Carmen Bergom. Revisiting the angiogenic switch: Host genetic modifiers induce non-productive angiogenesis and inhibit breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 782. doi:10.1158/1538-7445.AM2017-782