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Genetic Modifiers of the Breast Tumor Microenvironment.

ABSTRACT: Multiple nonmalignant cell types in the tumor microenvironment (TME) impact breast cancer risk, metastasis, and response to therapy, yet most heritable mechanisms that influence TME cell function and breast cancer outcomes are largely unknown. Breast cancer risk is ?30% heritable and >170 genetic loci have been associated with breast cancer traits. However, the majority of candidate genes have poorly defined mechanistic roles in breast cancer biology. Research indicates that breast cancer risk modifiers directly impact cancer cells, yet it is equally plausible that some modifier alleles impact the nonmalignant TME. The objective of this review is to examine the list of current breast cancer candidate genes that may modify breast cancer risk and outcome through the TME.

SUBMITTER: Flister MJ

PROVIDER: S-EPMC5990047 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Genetic Modifiers of the Breast Tumor Microenvironment.

Flister Michael J MJ Bergom Carmen C

Trends in cancer 20180508 6

Multiple nonmalignant cell types in the tumor microenvironment (TME) impact breast cancer risk, metastasis, and response to therapy, yet most heritable mechanisms that influence TME cell function and breast cancer outcomes are largely unknown. Breast cancer risk is ∼30% heritable and >170 genetic loci have been associated with breast cancer traits. However, the majority of candidate genes have poorly defined mechanistic roles in breast cancer biology. Research indicates that breast cancer risk m ...[more]

PMID: 29860987

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Project description:Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients.

Project description: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 SSIL2Rγ and SS.BN3IL2Rγ CXM strains.ResultsBreast 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.ConclusionsCollectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.

Dataset Information

Genetic Modifiers of the Breast Tumor Microenvironment.

Publications

Genetic Modifiers of the Breast Tumor Microenvironment.

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