TY - JOUR T1 - Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. JF - Sci Rep Y1 - 2015 A1 - Zhang, Pengju A1 - Lo, Alvin A1 - Huang, Yurong A1 - Huang, Ge A1 - Liang, Guozhou A1 - Mott, Joni A1 - Karpen, Gary H A1 - Blakely, Eleanor A A1 - Bissell, Mina J A1 - Barcellos-Hoff, Mary Helen A1 - A Snijders A1 - Jiang-Hua Mao KW - Animals KW - Breast Neoplasms KW - Cell Line, Tumor KW - Cytokines KW - Female KW - Genetic Predisposition to Disease KW - Mice KW - Mice, Inbred BALB C KW - Neoplasms, Radiation-Induced KW - Quantitative Trait Loci KW - Risk Factors KW - Transforming Growth Factor beta1 KW - Tumor Microenvironment AB -

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.

VL - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25747469?dopt=Abstract ER - TY - JOUR T1 - Densely ionizing radiation acts via the microenvironment to promote aggressive Trp53-null mammary carcinomas. JF - Cancer Res Y1 - 2014 A1 - Illa-Bochaca, Irineu A1 - Ouyang, Haoxu A1 - Tang, Jonathan A1 - Sebastiano, Christopher A1 - Jiang-Hua Mao A1 - Costes, Sylvain V A1 - Demaria, Sandra A1 - Barcellos-Hoff, Mary Helen KW - Animals KW - Biomarkers, Tumor KW - Cadherins KW - Female KW - Gene Expression Profiling KW - Keratins KW - Mammary Neoplasms, Experimental KW - Mice KW - Mice, Inbred BALB C KW - Proto-Oncogene Proteins p21(ras) KW - Radiation, Ionizing KW - Receptor, ErbB-2 KW - Receptors, Estrogen KW - Receptors, Notch KW - Stem Cells KW - Tumor Microenvironment KW - Tumor Suppressor Protein p53 AB -

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.

VL - 74 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25304265?dopt=Abstract ER - TY - JOUR T1 - Distinct luminal-type mammary carcinomas arise from orthotopic Trp53-null mammary transplantation of juvenile versus adult mice. JF - Cancer Res Y1 - 2014 A1 - Nguyen, David H A1 - Ouyang, Haoxu A1 - Jiang-Hua Mao A1 - Hlatky, Lynn A1 - Barcellos-Hoff, Mary Helen KW - Animals KW - Breast Neoplasms KW - Cell Transformation, Neoplastic KW - Cluster Analysis KW - Epithelium KW - Female KW - Gene Expression Regulation, Neoplastic KW - Humans KW - Mammary Glands, Human KW - Mammary Neoplasms, Experimental KW - Mice KW - Mice, Inbred BALB C KW - Phosphorylation KW - Receptors, Estrogen KW - Receptors, Somatomedin KW - Tumor Suppressor Protein p53 AB -

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.

VL - 74 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25281718?dopt=Abstract ER - TY - JOUR T1 - An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival. JF - Oncotarget Y1 - 2014 A1 - A Snijders A1 - Langley, Sasha A1 - Jiang-Hua Mao A1 - Bhatnagar, Sandhya A1 - Bjornstad, Kathleen A A1 - Rosen, Chris J A1 - Lo, Alvin A1 - Huang, Yurong A1 - Blakely, Eleanor A A1 - Karpen, Gary H A1 - Bissell, Mina J A1 - Wyrobek, Andrew J KW - Animals KW - Disease-Free Survival KW - Estrous Cycle KW - Female KW - Humans KW - Interferons KW - Mice KW - Mice, Inbred BALB C KW - Mice, Inbred C57BL KW - Neoplasm Metastasis KW - RNA, Messenger AB -

The concept that a breast cancer patient'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's risk for distant metastases.

VL - 5 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24994117?dopt=Abstract ER - TY - JOUR T1 - Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model. JF - Int J Oncol Y1 - 2013 A1 - Hung, Ming-Szu A1 - Xu, Zhidong A1 - Chen, Yu A1 - Smith, Emmanuel A1 - Jiang-Hua Mao A1 - Hsieh, David A1 - Lin, Yu-Ching A1 - Yang, Cheng-Ta A1 - Jablons, David M A1 - You, Liang KW - Animals KW - Apoptosis KW - Blotting, Western KW - Casein Kinase II KW - Enzyme Inhibitors KW - Female KW - Hematoxylin KW - Humans KW - Immunoenzyme Techniques KW - Lung Neoplasms KW - Mice KW - Mice, Inbred BALB C KW - Phosphorylation KW - Proto-Oncogene Proteins c-akt KW - T Cell Transcription Factor 1 KW - Tumor Cells, Cultured KW - Wnt Proteins KW - Xenograft Model Antitumor Assays AB -

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.

VL - 43 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24008396?dopt=Abstract ER - TY - JOUR T1 - Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility JF - PLoS One Y1 - 2012 A1 - A Snijders A1 - Marchetti, Francesco A1 - Bhatnagar, Sandhya A1 - Duru, Nadire A1 - Ju Han A1 - Hu, Zhi A1 - Jiang-Hua Mao A1 - Gray, Joe W A1 - Wyrobek, Andrew J KW - Animals KW - Breast Neoplasms KW - Dose-Response Relationship, Radiation KW - Female KW - Genetic Predisposition to Disease KW - Genomic Instability KW - Humans KW - Mice KW - Mice, Inbred BALB C KW - Mice, Inbred C57BL KW - Radiation, Ionizing KW - RNA, Messenger KW - Survival Analysis KW - Transcription, Genetic KW - Tumor Microenvironment AB -

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.

VL - 7 IS - 10 ER - TY - JOUR T1 - Low-dose ionizing radiation-induced blood plasma metabolic response in a diverse genetic mouse population. JF - Radiat Res Y1 - 2012 A1 - Lee, Do Yup A1 - Bowen, Benjamin P A1 - Nguyen, David H A1 - Parsa, Sara A1 - Huang, Yurong A1 - Jiang-Hua Mao A1 - Northen, Trent R KW - Animals KW - Blood KW - Crosses, Genetic KW - Dose-Response Relationship, Radiation KW - Female KW - Genetic Variation KW - Male KW - Metabolome KW - Mice KW - Mice, Inbred BALB C KW - Species Specificity KW - Transcriptome AB -

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.

VL - 178 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23051006?dopt=Abstract ER - TY - JOUR T1 - Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. JF - Cancer Cell Y1 - 2011 A1 - Nguyen, David H A1 - Oketch-Rabah, Hellen A A1 - Illa-Bochaca, Irineu A1 - Geyer, Felipe C A1 - Reis-Filho, Jorge S A1 - Jiang-Hua Mao A1 - Ravani, Shraddha A A1 - Zavadil, Jiri A1 - Borowsky, Alexander D A1 - Jerry, D Joseph A1 - Dunphy, Karen A A1 - Seo, Jae Hong A1 - Haslam, Sandra A1 - Medina, Daniel A1 - Barcellos-Hoff, Mary Helen KW - Animals KW - Breast Neoplasms KW - Cell Transformation, Neoplastic KW - Dose-Response Relationship, Radiation KW - Epithelial Cells KW - Female KW - Gene Expression Profiling KW - Gene Expression Regulation, Neoplastic KW - Gene Regulatory Networks KW - Mammary Glands, Animal KW - Mice KW - Mice, Inbred BALB C KW - Mice, Knockout KW - Neoplasms, Radiation-Induced KW - Radiation Chimera KW - Reaction Time KW - Receptors, Estrogen KW - Time Factors KW - Transforming Growth Factor beta1 KW - Tumor Burden KW - Tumor Microenvironment KW - Tumor Suppressor Protein p53 KW - Whole-Body Irradiation AB -

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.

VL - 19 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21575864?dopt=Abstract ER - TY - JOUR T1 - Mapping segmental and sequence variations among laboratory mice using BAC array CGH. JF - Genome Res Y1 - 2005 A1 - A Snijders A1 - Nowak, Norma J A1 - Huey, Bing A1 - Fridlyand, Jane A1 - Law, Sindy A1 - Conroy, Jeffrey A1 - Tokuyasu, Taku A1 - Demir, Kubilay A1 - Chiu, Readman A1 - Jiang-Hua Mao A1 - Jain, Ajay N A1 - Jones, Steven J M A1 - Balmain, Allan A1 - Pinkel, Daniel A1 - Albertson, Donna G KW - Animals KW - Chromosome Mapping KW - Chromosomes, Artificial, Bacterial KW - Crosses, Genetic KW - Gene Dosage KW - Genetic Markers KW - Genetic Variation KW - Genome KW - Mice KW - Mice, Inbred BALB C KW - Mice, Inbred C3H KW - Mice, Inbred C57BL KW - Mice, Inbred DBA KW - Mice, Inbred Strains KW - Nucleic Acid Hybridization KW - Oligonucleotide Array Sequence Analysis KW - Species Specificity AB -

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.

VL - 15 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/15687294?dopt=Abstract ER -