@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 {212, title = {Densely ionizing radiation acts via the microenvironment to promote aggressive Trp53-null mammary carcinomas.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Dec 1}, pages = {7137-48}, abstract = {

Densely ionizing radiation, which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared with sparsely ionizing radiation that is prevalent on earth. Here, we used a radiation chimera in which mice were exposed to densely ionizing 350 MeV/amu Si-particles, γ-radiation, or sham-irradiated and transplanted 3 days later with syngeneic Trp53-null mammary fragments. Trp53-null tumors arising in mice irradiated with Si-particles had a shorter median time to appearance and grew faster once detected compared with those in sham-irradiated or γ-irradiated mice. Tumors were further classified by markers keratin 8/18 (K18, KRT18), keratin 14 (K14, KRT14) and estrogen receptor (ER, ESR1), and expression profiling. Most tumors arising in sham-irradiated hosts were comprised of both K18- and K14-positive cells (K14/18) while those tumors arising in irradiated hosts were mostly K18. Keratin staining was significantly associated with ER status: K14/18 tumors were predominantly ER-positive, whereas K18 tumors were predominantly ER-negative. Genes differentially expressed in K18 tumors compared with K14/18 tumor were associated with ERBB2 and KRAS, metastasis, and loss of E-cadherin. Consistent with this, K18 tumors tended to grow faster and be more metastatic than K14/18 tumors, however, K18 tumors in particle-irradiated mice grew significantly larger and were more metastatic compared with sham-irradiated mice. An expression profile that distinguished K18 tumors arising in particle-irradiated mice compared with sham-irradiated mice was enriched in mammary stem cell, stroma, and Notch signaling genes. These data suggest that carcinogenic effects of densely ionizing radiation are mediated by the microenvironment, which elicits more aggressive tumors compared with similar tumors arising in sham-irradiated hosts.

}, keywords = {Animals, Biomarkers, Tumor, Cadherins, Female, Gene Expression Profiling, Keratins, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Proto-Oncogene Proteins p21(ras), Radiation, Ionizing, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Notch, Stem Cells, Tumor Microenvironment, Tumor Suppressor Protein p53}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-14-1212}, author = {Illa-Bochaca, Irineu and Ouyang, Haoxu and Tang, Jonathan and Sebastiano, Christopher and Jiang-Hua Mao and Costes, Sylvain V and Demaria, Sandra and Barcellos-Hoff, Mary Helen} } @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 {209, title = {An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival.}, journal = {Oncotarget}, volume = {5}, year = {2014}, month = {2014 Jun 30}, pages = {4011-25}, abstract = {

The concept that a breast cancer patient{\textquoteright}s menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight in this observation. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent gene cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient{\textquoteright}s risk for distant metastases.

}, keywords = {Animals, Disease-Free Survival, Estrous Cycle, Female, Humans, Interferons, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, RNA, Messenger}, issn = {1949-2553}, doi = {10.18632/oncotarget.2148}, author = {A Snijders and Langley, Sasha and Jiang-Hua Mao and Bhatnagar, Sandhya and Bjornstad, Kathleen A and Rosen, Chris J and Lo, Alvin and Huang, Yurong and Blakely, Eleanor A and Karpen, Gary H and Bissell, Mina J and Wyrobek, Andrew J} } @article {204, title = {Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model.}, journal = {Int J Oncol}, volume = {43}, year = {2013}, month = {2013 Nov}, pages = {1517-22}, abstract = {

Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2α in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer.

}, keywords = {Animals, Apoptosis, Blotting, Western, Casein Kinase II, Enzyme Inhibitors, Female, Hematoxylin, Humans, Immunoenzyme Techniques, Lung Neoplasms, Mice, Mice, Inbred BALB C, Phosphorylation, Proto-Oncogene Proteins c-akt, T Cell Transcription Factor 1, Tumor Cells, Cultured, Wnt Proteins, Xenograft Model Antitumor Assays}, issn = {1791-2423}, doi = {10.3892/ijo.2013.2087}, author = {Hung, Ming-Szu and Xu, Zhidong and Chen, Yu and Smith, Emmanuel and Jiang-Hua Mao and Hsieh, David and Lin, Yu-Ching and Yang, Cheng-Ta and Jablons, David M and You, Liang} } @article {78, title = {Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e45394}, abstract = {

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, \<10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p\<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.

}, keywords = {Animals, Breast Neoplasms, Dose-Response Relationship, Radiation, Female, Genetic Predisposition to Disease, Genomic Instability, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Radiation, Ionizing, RNA, Messenger, Survival Analysis, Transcription, Genetic, Tumor Microenvironment}, issn = {1932-6203}, doi = {10.1371/journal.pone.0045394}, author = {A Snijders and Marchetti, Francesco and Bhatnagar, Sandhya and Duru, Nadire and Ju Han and Hu, Zhi and Jiang-Hua Mao and Gray, Joe W and Wyrobek, Andrew J} } @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} } @article {147, title = {Mapping segmental and sequence variations among laboratory mice using BAC array CGH.}, journal = {Genome Res}, volume = {15}, year = {2005}, month = {2005 Feb}, pages = {302-11}, abstract = {

We used arrays of 2069 BACs (1303 nonredundant autosomal clones) to map sequence variation among Mus spretus (SPRET/Ei and SPRET/Glasgow) and Mus musculus (C3H/HeJ, BALB/cJ, 129/J, DBA/2J, NIH, FVB/N, and C57BL/6) strains. We identified 80 clones representing 74 autosomal loci of copy number variation (|log(2)ratio| >/= 0.4). These variant loci distinguish laboratory strains. By FISH mapping, we determined that 63 BACs mapped to a single site on C57BL/6J chromosomes, while 17 clones mapped to multiple chromosomes (n = 16) or multiple sites on one chromosome (n = 1). We also show that small ratio changes (Delta log(2)ratio approximately 0.1) distinguish homozygous and heterozygous regions of the genome in interspecific backcross mice, providing an efficient method for genotyping progeny of backcrosses.

}, keywords = {Animals, Chromosome Mapping, Chromosomes, Artificial, Bacterial, Crosses, Genetic, Gene Dosage, Genetic Markers, Genetic Variation, Genome, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred Strains, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Species Specificity}, issn = {1088-9051}, doi = {10.1101/gr.2902505}, author = {A Snijders and Nowak, Norma J and Huey, Bing and Fridlyand, Jane and Law, Sindy and Conroy, Jeffrey and Tokuyasu, Taku and Demir, Kubilay and Chiu, Readman and Jiang-Hua Mao and Jain, Ajay N and Jones, Steven J M and Balmain, Allan and Pinkel, Daniel and Albertson, Donna G} }