@article {214, title = {Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation.}, journal = {Int J Genomics}, volume = {2015}, year = {2015}, month = {2015}, pages = {461038}, abstract = {

Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed after LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.

}, issn = {2314-436X}, doi = {10.1155/2015/461038}, author = {Tang, Jonathan and Huang, Yurong and Nguyen, David H and Costes, Sylvain V and A Snijders and Jiang-Hua Mao} } @article {213, title = {Distinct luminal-type mammary carcinomas arise from orthotopic Trp53-null mammary transplantation of juvenile versus adult mice.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Dec 1}, pages = {7149-58}, abstract = {

Age and physiologic status, such as menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently transplanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53-null mammary tissue fragments and monitored for one year. Tumors arose sooner from adult hosts (AH) compared with juvenile hosts (JH). However, compared with AH tumors, JH tumors grew several times faster, were more perfused, exhibited a two-fold higher mitotic index, and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were estrogen receptor (ER)-positive (80\% JH vs. 70\% AH), but JH tumors were significantly more ER-immunoreactive (P = 0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across datasets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer.

}, keywords = {Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Cluster Analysis, Epithelium, Female, Gene Expression Regulation, Neoplastic, Humans, Mammary Glands, Human, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Phosphorylation, Receptors, Estrogen, Receptors, Somatomedin, Tumor Suppressor Protein p53}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-14-1440}, author = {Nguyen, David H and Ouyang, Haoxu and Jiang-Hua Mao and Hlatky, Lynn and Barcellos-Hoff, Mary Helen} } @article {207, title = {Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors.}, journal = {Stem Cells}, volume = {32}, year = {2014}, month = {2014 Mar}, pages = {649-61}, abstract = {

Children exposed to ionizing radiation have a substantially greater breast cancer risk than adults; the mechanism for this strong age dependence is not known. Here we show that pubertal murine mammary glands exposed to sparsely or densely ionizing radiation exhibit enrichment of mammary stem cell and Notch pathways, increased mammary repopulating activity indicative of more stem cells, and propensity to develop estrogen receptor (ER) negative tumors thought to arise from stem cells. We developed a mammary lineage agent-based model (ABM) to evaluate cell inactivation, self-renewal, or dedifferentiation via epithelial-mesenchymal transition (EMT) as mechanisms by which radiation could increase stem cells. ABM rejected cell inactivation and predicted increased self-renewal would only affect juveniles while dedifferentiation could act in both juveniles and adults. To further test self-renewal versus dedifferentiation, we used the MCF10A human mammary epithelial cell line, which recapitulates ductal morphogenesis in humanized fat pads, undergoes EMT in response to radiation and transforming growth factor β (TGFβ) and contains rare stem-like cells that are Let-7c negative or express both basal and luminal cytokeratins. ABM simulation of population dynamics of double cytokeratin cells supported increased self-renewal in irradiated MCF10A treated with TGFβ. Radiation-induced Notch concomitant with TGFβ was necessary for increased self-renewal of Let-7c negative MCF10A cells but not for EMT, indicating that these are independent processes. Consistent with these data, irradiating adult mice did not increase mammary repopulating activity or ER-negative tumors. These studies suggest that irradiation during puberty transiently increases stem cell self-renewal, which increases susceptibility to developing ER-negative breast cancer.

}, keywords = {Aging, Animals, Biomarkers, Cell Line, Cell Lineage, Cell Proliferation, Computer Simulation, Dose-Response Relationship, Radiation, Epithelial Cells, Female, Humans, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mice, Morphogenesis, Radiation, Ionizing, Receptors, Estrogen, Receptors, Notch, Stem Cells, Transforming Growth Factor beta}, issn = {1549-4918}, doi = {10.1002/stem.1533}, author = {Tang, Jonathan and Fernandez-Garcia, Ignacio and Vijayakumar, Sangeetha and Martinez-Ruis, Haydeliz and Illa-Bochaca, Irineu and Nguyen, David H and Jiang-Hua Mao and Costes, Sylvain V and Barcellos-Hoff, Mary Helen} } @article {199, title = {Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes.}, journal = {Clin Cancer Res}, volume = {19}, year = {2013}, month = {2013 Mar 15}, pages = {1353-62}, abstract = {

PURPOSE: Ionizing radiation is a well-established carcinogen in rodent models and a risk factor associated with human cancer. We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53-null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in na{\"\i}ve hosts. We asked whether expression metaprofiles could discern radiation-preceded human cancer or be informative in sporadic breast cancers.

EXPERIMENTAL DESIGN: Affymetrix microarray gene expression data from 56 Trp53-null mammary tumors were used to define gene profiles and a centroid that discriminates tumors arising in irradiated hosts. These were applied to publicly available human cancer datasets.

RESULTS: Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages, and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation-preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor-negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGF-β levels showed that inflammation was robustly associated with claudin-low tumors.

CONCLUSIONS: Detection of radiation-preceded human cancer by the irradiated host metaprofile raises possibilities of assessing human cancer etiology. Moreover, the association of the irradiated host metaprofiles with estrogen receptor-negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers.

}, keywords = {Animals, Breast Neoplasms, Female, Gene Expression Regulation, Neoplastic, Humans, Mammary Neoplasms, Animal, Mice, Radiation, Ionizing, Transcriptome, Tumor Microenvironment, Tumor Suppressor Protein p53}, issn = {1078-0432}, doi = {10.1158/1078-0432.CCR-12-3554}, author = {Nguyen, David H and Fredlund, Erik and Zhao, Wei and Perou, Charles M and Balmain, Allan and Jiang-Hua Mao and Barcellos-Hoff, Mary Helen} } @article {193, title = {Low-dose ionizing radiation-induced blood plasma metabolic response in a diverse genetic mouse population.}, journal = {Radiat Res}, volume = {178}, year = {2012}, month = {2012 Dec}, pages = {551-5}, abstract = {

Understanding the biological effects and biochemical mechanisms of low-dose ionizing radiation (LDIR) is important for setting exposure limits for the safe use of nuclear power and medical diagnostic procedures. Although several studies have highlighted the effects of ionizing radiation on metabolism, most studies have focused on uniform genetic mouse populations. Here, we report the metabolic response to LDIR (10 cGy X ray) on a genetically diverse mouse population (142 mice) generated from a cross of radiation-sensitive (BALB/c) and radiation-resistant (SPRET/EiJ) parental strains. GC-TOF profiling of plasma metabolites was used to compare exposed vs. sham animals. From this, 16 metabolites were significantly altered in the LDIR treated vs. sham group. Use of two significantly altered metabolites, thymine and 2-monostearin, was found to effectively segregate the two treatments. Multivariate statistical analysis was used to identify genetic polymorphisms correlated with metabolite abundance (e.g., amino acids, fatty acids, nucleotides and TCA cycle intermediates). Genetic analysis of metabolic phenotypes showed suggestive linkages for fatty acid and amino acid metabolism. However, metabolite abundance was found to be a function of low-dose ionizing radiation exposure, and not of the underlying genetic variation.

}, keywords = {Animals, Blood, Crosses, Genetic, Dose-Response Relationship, Radiation, Female, Genetic Variation, Male, Metabolome, Mice, Mice, Inbred BALB C, Species Specificity, Transcriptome}, issn = {1938-5404}, doi = {10.1667/RR2990.1}, author = {Lee, Do Yup and Bowen, Benjamin P and Nguyen, David H and Parsa, Sara and Huang, Yurong and Jiang-Hua Mao and Northen, Trent R} } @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} }