@article {219, title = {Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {8919}, abstract = {

The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

}, keywords = {Animals, Breast Neoplasms, Cell Line, Tumor, Cytokines, Female, Genetic Predisposition to Disease, Mice, Mice, Inbred BALB C, Neoplasms, Radiation-Induced, Quantitative Trait Loci, Risk Factors, Transforming Growth Factor beta1, Tumor Microenvironment}, issn = {2045-2322}, doi = {10.1038/srep08919}, author = {Zhang, Pengju and Lo, Alvin and Huang, Yurong and Huang, Ge and Liang, Guozhou and Mott, Joni and Karpen, Gary H and Blakely, Eleanor A and Bissell, Mina J and Barcellos-Hoff, Mary Helen and A Snijders and Jiang-Hua Mao} } @article {210, title = {Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma.}, journal = {Cell Rep}, volume = {9}, year = {2014}, month = {2014 Nov 6}, pages = {1034-46}, abstract = {

The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene-expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy.

}, keywords = {Animals, Apoptosis, Arginase, Brain Neoplasms, Cell Line, Tumor, Cell Survival, Chromosomes, Mammalian, gamma-Aminobutyric Acid, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Humans, Mice, Molecular Targeted Therapy, Neuroblastoma, Quantitative Trait Loci, Receptors, GABA-A, Survival Analysis}, issn = {2211-1247}, doi = {10.1016/j.celrep.2014.09.046}, author = {Hackett, Christopher S and Quigley, David A and Wong, Robyn A and Chen, Justin and Cheng, Christine and Song, Young K and Wei, Jun S and Pawlikowska, Ludmila and Bao, Yun and Goldenberg, David D and Nguyen, Kim and Gustafson, W Clay and Rallapalli, Sundari K and Cho, Yoon-Jae and Cook, James M and Kozlov, Serguei and Jiang-Hua Mao and Van Dyke, Terry and Kwok, Pui-Yan and Khan, Javed and Balmain, Allan and Fan, QiWen and Weiss, William A} } @article {176, title = {Cancer evolution and individual susceptibility.}, journal = {Integr Biol (Camb)}, volume = {3}, year = {2011}, month = {2011 Apr}, pages = {316-28}, abstract = {

Cancer susceptibility is due to interactions between inherited genetic factors and exposure to environmental carcinogens. The genetic component is constituted mainly by weakly acting low-penetrance genetic variants that interact among themselves, as well as with the environment. These low susceptibility genes can be categorized into two main groups: one includes those that control intrinsic tumor cell activities (i.e. apoptosis, proliferation or DNA repair), and the other contains those that modulate the function of extrinsic tumor cell compartments (i.e. stroma, angiogenesis, or endocrine and immune systems). Genome-Wide Association Studies (GWAS) of human populations have identified numerous genetic loci linked with cancer risk and behavior, but nevertheless the major component of cancer heritability remains to be explained. One reason may be that GWAS cannot readily capture gene-gene or gene-environment interactions. Mouse model approaches offer an alternative or complementary strategy, because of our ability to control both the genetic and environmental components of risk. Recently developed genetic tools, including high-throughput technologies such as SNP, CGH and gene expression microarrays, have led to more powerful strategies for refining quantitative trait loci (QTL) and identifying the critical genes. In particular, the cross-species approaches will help to refine locations of QTLs, and reveal their genetic and environmental interactions. The identification of human tumor susceptibility genes and discovery of their roles in carcinogenesis will ultimately be important for the development of methods for prediction of risk, diagnosis, prevention and therapy for human cancers.

}, keywords = {Animals, Disease Susceptibility, Environmental Exposure, Genome-Wide Association Study, Humans, Neoplasms, Quantitative Trait Loci}, issn = {1757-9708}, doi = {10.1039/c0ib00094a}, author = {Perez-Losada, Jesus and Castellanos-Mart{\'\i}n, Andr{\'e}s and Jiang-Hua Mao} } @article {165, title = {Genetic architecture of mouse skin inflammation and tumour susceptibility.}, journal = {Nature}, volume = {458}, year = {2009}, month = {2009 Mar 26}, pages = {505-8}, abstract = {

Germline polymorphisms in model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer. Mice of the Mus spretus species are resistant to tumour development, and crosses between M. spretus and susceptible Mus musculus strains have been used to map locations of genetic variants that contribute to skin cancer susceptibility. We have integrated germline polymorphisms with gene expression in normal skin from a M. musculus x M. spretus backcross to generate a network view of the gene expression architecture of mouse skin. Here we demonstrate how this approach identifies expression motifs that contribute to tissue organization and biological functions related to inflammation, haematopoiesis, cell cycle control and tumour susceptibility. Motifs associated with inflammation, epidermal barrier function and proliferation are differentially regulated in backcross mice susceptible or resistant to tumour development. The intestinal stem cell marker Lgr5 is identified as a candidate master regulator of the hair follicle, and the vitamin D receptor (Vdr) is linked to coordinated control of epidermal barrier function, inflammation and tumour susceptibility.

}, keywords = {Animals, Cell Cycle, Crosses, Genetic, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Hair Follicle, Hematopoiesis, Inflammation, Male, Mice, Quantitative Trait Loci, Receptors, Calcitriol, Receptors, G-Protein-Coupled, Skin, Skin Neoplasms}, issn = {1476-4687}, doi = {10.1038/nature07683}, author = {Quigley, David A and To, Minh D and Perez-Losada, Jesus and Pelorosso, Facundo G and Jiang-Hua Mao and Nagase, Hiroki and Ginzinger, David G and Balmain, Allan} } @article {139, title = {Genomic approaches to identification of tumour-susceptibility genes using mouse models.}, journal = {Curr Opin Genet Dev}, volume = {13}, year = {2003}, month = {2003 Feb}, pages = {14-9}, abstract = {

Individual susceptibility to cancer in humans is determined by complex interactions between germline genetic variation and levels of exposure to environmental carcinogens or tumour promoters. Only a small fraction of cancer susceptibility is inherited in a Mendelian manner (high-penetrance familial cancer), and most tumours result from the combined effects of many gene-gene and gene-environment interactions. The sequencing of the mouse genome provides new approaches to one of the most challenging tasks of cancer genetics today.

}, keywords = {Animals, Chromosome Mapping, Disease Models, Animal, Genetic Predisposition to Disease, Genomics, Humans, Mice, Neoplasms, Oligonucleotide Array Sequence Analysis, Quantitative Trait Loci}, issn = {0959-437X}, author = {Jiang-Hua Mao and Balmain, Allan} } @article {138, title = {Novel approaches to identify low-penetrance cancer susceptibility genes using mouse models.}, journal = {Recent Results Cancer Res}, volume = {163}, year = {2003}, month = {2003}, pages = {19-27; discussion 264-6}, abstract = {

Studies of cancer predisposition have largely concentrated on the role of high-penetrance susceptibility genes. Less than 10\% of the total human tumor burden, however, is accounted for by mutations in these genes. More genetic variation in cancer risk is likely to be due to commoner but lower penetrance alleles. In man, such modifier genes will be difficult to find since they do not segregate as single Mendelian traits. The mouse offers a powerful system for studying polygenic traits such as cancer and has been widely used for this purpose. Novel approaches that might accelerate the identification of these low-penetrance cancer susceptibility genes by using mouse models will be discussed.

}, keywords = {Alleles, Animals, Disease Models, Animal, Genes, Tumor Suppressor, Genetic Linkage, Genetic Predisposition to Disease, Humans, Multifactorial Inheritance, Mutation, Neoplasms, Penetrance, Phenotype, Quantitative Trait Loci}, issn = {0080-0015}, author = {de Koning, John P and Jiang-Hua Mao and Balmain, Allan} }