@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 {222, title = {Low-dose radiation cancer susceptibility models.}, journal = {Aging (Albany NY)}, volume = {7}, year = {2015}, month = {2015 Jun}, pages = {352-3}, keywords = {Dose-Response Relationship, Radiation, Genetic Predisposition to Disease, Humans, Models, Biological, Neoplasms, Radiation-Induced, Risk Factors}, issn = {1945-4589}, doi = {10.18632/aging.100767}, author = {Jiang-Hua Mao and A Snijders} } @article {283, title = {Understanding cancer development processes after HZE-particle exposure: roles of ROS, DNA damage repair and inflammation.}, journal = {Radiat Res}, volume = {183}, year = {2015}, month = {2015 Jan}, pages = {1-26}, abstract = {

During space travel astronauts are exposed to a variety of radiations, including galactic cosmic rays composed of high-energy protons and high-energy charged (HZE) nuclei, and solar particle events containing low- to medium-energy protons. Risks from these exposures include carcinogenesis, central nervous system damage and degenerative tissue effects. Currently, career radiation limits are based on estimates of fatal cancer risks calculated using a model that incorporates human epidemiological data from exposed populations, estimates of relative biological effectiveness and dose-response data from relevant mammalian experimental models. A major goal of space radiation risk assessment is to link mechanistic data from biological studies at NASA Space Radiation Laboratory and other particle accelerators with risk models. Early phenotypes of HZE exposure, such as the induction of reactive oxygen species, DNA damage signaling and inflammation, are sensitive to HZE damage complexity. This review summarizes our current understanding of critical areas within the DNA damage and oxidative stress arena and provides insight into their mechanistic interdependence and their usefulness in accurately modeling cancer and other risks in astronauts exposed to space radiation. Our ultimate goals are to examine potential links and crosstalk between early response modules activated by charged particle exposure, to identify critical areas that require further research and to use these data to reduced uncertainties in modeling cancer risk for astronauts. A clearer understanding of the links between early mechanistic aspects of high-LET response and later surrogate cancer end points could reveal key nodes that can be therapeutically targeted to mitigate the health effects from charged particle exposures.

}, keywords = {Animals, Carcinogenesis, Cosmic Radiation, DNA Damage, DNA Repair, Environmental Exposure, Humans, Inflammation, Neoplasms, Radiation-Induced, Reactive Oxygen Species}, issn = {1938-5404}, doi = {10.1667/RR13804.1}, author = {Sridharan, D M and Asaithamby, A and Bailey, S M and Costes, S V and Doetsch, P W and Dynan, W S and Kronenberg, A and Rithidech, K N and Saha, J and A Snijders and Werner, E and Wiese, C and Cucinotta, F A and Pluth, J M} } @article {196, title = {Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development.}, journal = {Aging (Albany NY)}, volume = {5}, year = {2013}, month = {2013 Feb}, pages = {111-9}, abstract = {

FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short-term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice but not in p53 single heterozygous (p53+/-) mice. Tumor latency of rapamycin treated Fbxw7+/-p53+/- mice is remarkably similar to those of p53+/- mice while placebo treatedFbxw7+/-p53+/- mice develop tumor significantly earlier than placebo treated p53+/- mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development.

}, keywords = {Animals, Cell Transformation, Neoplastic, F-Box Proteins, Genes, Tumor Suppressor, Mice, Mutation, Neoplasms, Radiation-Induced, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases}, issn = {1945-4589}, doi = {10.18632/aging.100535}, author = {Liu, Yueyong and Huang, Yurong and Wang, Zeran and Huang, Yong and Li, Xiaohua and Louie, Alexander and Wei, Guangwei and Jiang-Hua Mao} } @article {185, title = {Hipk2 cooperates with p53 to suppress γ-ray radiation-induced mouse thymic lymphoma.}, journal = {Oncogene}, volume = {31}, year = {2012}, month = {2012 Mar 1}, pages = {1176-80}, abstract = {

A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53+/- and p53-/- mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2). More than 30\% of radiation-induced tumors from both p53+/- and p53-/- mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by γ-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene.

}, keywords = {Animals, Carrier Proteins, Cell Transformation, Neoplastic, Chromosomes, Mammalian, Gamma Rays, Gene Expression Regulation, Neoplastic, Loss of Heterozygosity, Lymphoma, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasms, Radiation-Induced, Protein Binding, Protein-Serine-Threonine Kinases, Thymus Neoplasms, Tumor Suppressor Protein p53}, issn = {1476-5594}, doi = {10.1038/onc.2011.306}, author = {Jiang-Hua Mao and Wu, D and Kim, I-J and Kang, H C and Wei, G and Climent, J and Kumar, A and Pelorosso, F G and DelRosario, R and Huang, E J and Balmain, A} } @article {188, title = {Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.}, journal = {Mol Cancer Res}, volume = {10}, year = {2012}, month = {2012 Jun}, pages = {834-44}, abstract = {

The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.

}, keywords = {Animals, Aurora Kinase A, Aurora Kinases, Binding Sites, Blotting, Western, Cell Line, F-Box Proteins, Female, Gamma Rays, Glycogen Synthase Kinase 3, HCT116 Cells, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neoplasms, Radiation-Induced, NIH 3T3 Cells, Protein Binding, Protein-Serine-Threonine Kinases, PTEN Phosphohydrolase, Time Factors, Ubiquitin, Ubiquitin-Protein Ligases}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-12-0025}, author = {Kwon, Yong-Won and Kim, Il-Jin and Wu, Di and Lu, Jing and Stock, William A and Liu, Yueyong and Huang, Yurong and Kang, Hio Chung and DelRosario, Reyno and Jen, Kuang-Yu and Perez-Losada, Jesus and Wei, Guangwei and Balmain, Allan and Jiang-Hua Mao} } @article {184, title = {Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas.}, journal = {Blood}, volume = {119}, year = {2012}, month = {2012 Jan 19}, pages = {805-9}, abstract = {

T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.

}, keywords = {Animals, Disease Models, Animal, F-Box Proteins, Female, Loss of Heterozygosity, Male, Mice, Mice, Knockout, Mutation, Neoplasms, Radiation-Induced, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein Structure, Tertiary, Real-Time Polymerase Chain Reaction, Receptor, Notch1, RNA, Messenger, Thymus Neoplasms, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases}, issn = {1528-0020}, doi = {10.1182/blood-2011-01-327619}, author = {Jen, Kuang-Yu and Song, Ihn Young and Banta, Karl Luke and Wu, Di and Jiang-Hua Mao and Balmain, Allan} } @article {177, title = {Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type.}, journal = {Cancer Cell}, volume = {19}, year = {2011}, month = {2011 May 17}, pages = {640-51}, abstract = {

Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ, and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus, the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.

}, keywords = {Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Dose-Response Relationship, Radiation, Epithelial Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Mammary Glands, Animal, Mice, Mice, Inbred BALB C, Mice, Knockout, Neoplasms, Radiation-Induced, Radiation Chimera, Reaction Time, Receptors, Estrogen, Time Factors, Transforming Growth Factor beta1, Tumor Burden, Tumor Microenvironment, Tumor Suppressor Protein p53, Whole-Body Irradiation}, issn = {1878-3686}, doi = {10.1016/j.ccr.2011.03.011}, author = {Nguyen, David H and Oketch-Rabah, Hellen A and Illa-Bochaca, Irineu and Geyer, Felipe C and Reis-Filho, Jorge S and Jiang-Hua Mao and Ravani, Shraddha A and Zavadil, Jiri and Borowsky, Alexander D and Jerry, D Joseph and Dunphy, Karen A and Seo, Jae Hong and Haslam, Sandra and Medina, Daniel and Barcellos-Hoff, Mary Helen} } @article {168, title = {An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis.}, journal = {Oncogene}, volume = {29}, year = {2010}, month = {2010 May 6}, pages = {2659-71}, abstract = {

There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

}, keywords = {Acetylation, Animals, Binding Sites, Cell Division, Chromosome Fragile Sites, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, G2 Phase, Histone Deacetylase 1, Humans, Mice, Neoplasms, Radiation-Induced, NIH 3T3 Cells, Tumor Suppressor Proteins, Ubiquitination}, issn = {1476-5594}, doi = {10.1038/onc.2010.19}, author = {Li, Z and Zhang, Q and Jiang-Hua Mao and Weise, A and Mrasek, K and Fan, X and Zhang, X and Liehr, T and Lu, K H and Balmain, A and Cai, W-W} } @article {155, title = {Crosstalk between Aurora-A and p53: frequent deletion or downregulation of Aurora-A in tumors from p53 null mice.}, journal = {Cancer Cell}, volume = {11}, year = {2007}, month = {2007 Feb}, pages = {161-73}, abstract = {

The Aurora-A kinase gene is amplified in a subset of human tumors and in radiation-induced lymphomas from p53 heterozygous mice. Normal tissues from p53-/- mice have increased Aurora-A protein levels, but lymphomas from these mice exhibit heterozygous deletions of Aurora-A and/or reduced protein expression. A similar correlation between low p53 levels and Aurora-A gene deletions and expression is found in human breast cancer cell lines. In vitro studies using mouse embryo fibroblasts demonstrate that inhibition of Aurora-A can have either positive or negative effects on cell growth as a function of p53 status. These data have implications for the design of approaches to targeted cancer therapy involving the crosstalk between Aurora-A kinase and p53 pathways.

}, keywords = {Animals, Apoptosis, Aurora Kinase A, Aurora Kinases, Breast Neoplasms, Cells, Cultured, Down-Regulation, Embryo, Mammalian, Female, Fibroblasts, Gene Deletion, Gene Dosage, Gene Expression Profiling, Genomic Instability, Heterozygote, Lymphoma, Male, Mice, Mice, Knockout, Microarray Analysis, Neoplasms, Radiation-Induced, Protein-Serine-Threonine Kinases, Survival Rate, Thymus Neoplasms, Tumor Suppressor Protein p53, Whole-Body Irradiation}, issn = {1535-6108}, doi = {10.1016/j.ccr.2006.11.025}, author = {Jiang-Hua Mao and Wu, Di and Perez-Losada, Jesus and Jiang, Tao and Li, Qian and Neve, Richard M and Gray, Joe W and Cai, Wei-Wen and Balmain, Allan} } @article {152, title = {Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice.}, journal = {Oncogene}, volume = {24}, year = {2005}, month = {2005 Nov 24}, pages = {7924-34}, abstract = {

Although radiation can directly induce DNA damage and is a known human and animal carcinogen, the number of genetic changes in radiation-induced tumors, and the pathways responsible for generating them, are unknown. We have used high-density BAC arrays covering >95\% of the mouse genome for analysis of genomic patterns of aberrations in spontaneous and radiation-induced mouse lymphomas. The majority of radiation-induced tumors exhibit one of three {\textquoteright}signatures{\textquoteright} based on gene copy number changes. Some exhibit extensive scrambling of the genome, with very high numbers of recurrent gains and losses. Two other signatures are characterized by excess gains but relatively few losses, or vice versa. Changes in spontaneous tumors often involve whole chromosomes, whereas radiation-induced tumors exhibit a high frequency of localized deletion/amplification events. The number of copy number abnormalities does not correlate with the latency or pathology of the tumors. We propose that specific early events following radiation exposure induce changes in {\textquoteright}caretaker{\textquoteright} genes that control specific downstream pathways involved in DNA damage repair. The nature of these early events may determine the overall genomic signature observed in the resulting tumor.

}, keywords = {Animals, DNA Damage, DNA Repair, Female, Gene Amplification, Gene Deletion, Gene Expression Profiling, Genes, p53, Genomic Instability, Lymphoma, Male, Mice, Mice, Inbred C57BL, Neoplasms, Radiation-Induced, Thymus Neoplasms}, issn = {0950-9232}, doi = {10.1038/sj.onc.1208926}, author = {Jiang-Hua Mao and Li, Jiangzhen and Jiang, Tao and Li, Qian and Wu, Di and Perez-Losada, Jesus and DelRosario, Reyno and Peterson, Leif and Balmain, Allan and Cai, Wei-Wen} } @article {150, title = {p63 and p73 do not contribute to p53-mediated lymphoma suppressor activity in vivo.}, journal = {Oncogene}, volume = {24}, year = {2005}, month = {2005 Aug 18}, pages = {5521-4}, abstract = {

p53 is one of the most important tumor suppressor genes in human cancer, but the roles of its homologues p63 and p73 in tumor suppression, alone or in collaboration with p53, remains controversial. Both p63 and p73 can be deregulated after DNA damage, and induce cell cycle arrest and apoptosis, but mice carrying inactive alleles of these genes do not develop spontaneous tumors. Since heterozygous loss of p53 confers strong sensitization to radiation-induced lymphoma development, we investigated the possibility that radiation exposure may reveal previously undetected tumor suppressor properties in p63 or p73, alone or in combination with p53. Animals heterozygous for p63 or p73, as well as both double heterozygous p53/p63 or p53/p73 mice, showed no significant differences in tumor latency, spectrum or frequency after gamma-radiation, compared to their control counterparts. Deletions were found near the p63 locus on chromosome 16 in radiation-induced tumors, but these frequently included the knockout allele. No deletions or LOH involving the p73 gene were detected, and expression of both genes was maintained in the tumors. We conclude that p53 homologues do not contribute to p53 tumor suppressor activity in lymphoma development.

}, keywords = {Animals, Base Sequence, DNA-Binding Proteins, Genes, Tumor Suppressor, Loss of Heterozygosity, Lymphoma, Mice, Mice, Knockout, Molecular Sequence Data, Neoplasms, Radiation-Induced, Nuclear Proteins, Phosphoproteins, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators, Tumor Suppressor Protein p53, Tumor Suppressor Proteins}, issn = {0950-9232}, doi = {10.1038/sj.onc.1208799}, author = {Perez-Losada, Jesus and Wu, Di and DelRosario, Reyno and Balmain, Allan and Jiang-Hua Mao} } @article {142, title = {Genetic interactions between Pten and p53 in radiation-induced lymphoma development.}, journal = {Oncogene}, volume = {22}, year = {2003}, month = {2003 Nov 20}, pages = {8379-85}, abstract = {

Genetic analysis of radiation-induced lymphomas from p53 heterozygous or null mice has revealed a high frequency of genetic alterations on mouse chromosome 19. Detailed microsatellite analysis of chromosome 19 deletions identified three independent regions of loss of heterozygosity, one of which was refined to a 0.3 Mb interval that contained the Pten tumor suppressor gene. More than 50\% of radiation-induced tumors from p53+/- and p53-/- mice showed heterozygous loss of one Pten allele. In most cases, the remaining allele was wild type and expressed, suggesting that Pten is a haploinsufficient tumor suppressor gene for mouse lymphoma development. This conclusion was supported by the detection of specific intragenic deletions in Pten in tumors that retained one wild-type allele. Pten heterozygous mice were just as sensitive as p53+/- mice to induction of tumors by radiation, and surprisingly, the double p53+/-Pten+/-mice were equivalent to p53 null mice in radiation sensitivity. Despite the fact that Pten appears to be a haploinsufficient tumor suppressor gene, most tumors from both the single and double heterozygous mice had lost the remaining wild-type allele. The mechanism of loss in all cases involved the complete chromosome, suggesting that it is driven by other tumor suppressor genes on this chromosome. This sensitized screen therefore identified complementary roles for Pten and p53 pathways in suppression of tumor development induced by radiation exposure.

}, keywords = {Animals, Blotting, Western, Loss of Heterozygosity, Lymphoma, Mice, Neoplasms, Radiation-Induced, Phosphoric Monoester Hydrolases, PTEN Phosphohydrolase, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins}, issn = {0950-9232}, doi = {10.1038/sj.onc.1207083}, author = {Jiang-Hua Mao and Wu, Di and Perez-Losada, Jesus and Nagase, Hiroki and DelRosario, Reyno and Balmain, Allan} }