@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 {281, title = {Nanosensor dosimetry of mouse blood proteins after exposure to ionizing radiation.}, journal = {Sci Rep}, volume = {3}, year = {2013}, month = {2013}, pages = {2234}, abstract = {

Giant magnetoresistive (GMR) nanosensors provide a novel approach for measuring protein concentrations in blood for medical diagnosis. Using an in vivo mouse radiation model, we developed protocols for measuring Flt3 ligand (Flt3lg) and serum amyloid A1 (Saa1) in small amounts of blood collected during the first week after X-ray exposures of sham, 0.1, 1, 2, 3, or 6 Gy. Flt3lg concentrations showed excellent dose discrimination at >= 1 Gy in the time window of 1 to 7 days after exposure except 1 Gy at day 7. Saa1 dose response was limited to the first two days after exposure. A multiplex assay with both proteins showed improved dose classification accuracy. Our magneto-nanosensor assay demonstrates the dose and time responses, low-dose sensitivity, small volume requirements, and rapid speed that have important advantages in radiation triage biodosimetry.

}, keywords = {Animals, Biomarkers, Biosensing Techniques, Blood Proteins, Dose-Response Relationship, Radiation, Female, Male, Membrane Proteins, Mice, Nanotechnology, Radiation, Ionizing, Radiometry, Reproducibility of Results, Serum Amyloid A Protein, Time Factors}, issn = {2045-2322}, doi = {10.1038/srep02234}, author = {Kim, Dokyoon and Marchetti, Francesco and Chen, Zuxiong and Zaric, Sasa and Wilson, Robert J and Hall, Drew A and Gaster, Richard S and Lee, Jung-Rok and Wang, Junyi and Osterfeld, Sebastian J and Yu, Heng and White, Robert M and Blakely, William F and Peterson, Leif E and Bhatnagar, Sandhya and Mannion, Brandon and Tseng, Serena and Roth, Kristen and Coleman, Matthew and A Snijders and Wyrobek, Andrew J and Wang, Shan X} } @article {280, title = {DNA repair and cell cycle biomarkers of radiation exposure and inflammation stress in human blood.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e48619}, abstract = {

DNA damage and repair are hallmarks of cellular responses to ionizing radiation. We hypothesized that monitoring the expression of DNA repair-associated genes would enhance the detection of individuals exposed to radiation versus other forms of physiological stress. We employed the human blood ex vivo radiation model to investigate the expression responses of DNA repair genes in repeated blood samples from healthy, non-smoking men and women exposed to 2 Gy of X-rays in the context of inflammation stress mimicked by the bacterial endotoxin lipopolysaccharide (LPS). Radiation exposure significantly modulated the transcript expression of 12 genes of 40 tested (2.2E-06

}, keywords = {Adult, Biomarkers, Cell Cycle, DNA Repair, Dose-Response Relationship, Radiation, Female, Gene Expression Regulation, Humans, Inflammation, Lipopolysaccharides, Male, Middle Aged, Phosphorylation, Predictive Value of Tests, Reproducibility of Results, RNA, Messenger, Stress, Physiological, Time Factors, Transcription, Genetic, X-Rays, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0048619}, author = {Budworth, Helen and A Snijders and Marchetti, Francesco and Mannion, Brandon and Bhatnagar, Sandhya and Kwoh, Ely and Tan, Yuande and Wang, Shan X and Blakely, William F and Coleman, Matthew and Peterson, Leif and Wyrobek, Andrew J} } @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} }