55 research outputs found
Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition
Runx1 is a well characterized transcription factor essential for hematopoietic differentiation and Runx1 mutations are the cause of leukemias. Runx1 is highly expressed in normal epithelium of most glands and recently has been associated with solid tumors. Notably, the function of Runx1 in the mammary gland and how it is involved in initiation and progression of breast cancer is still unclear. Here we demonstrate the consequences of Runx1 loss in normal mammary epithelial and breast cancer cells. We first observed that Runx1 is decreased in tumorigenic and metastatic breast cancer cells. We also observed loss of Runx1 expression upon induction of epithelial-mesenchymal transition (EMT) in MCF10A (normal-like) cells. Furthermore depletion of Runx1 in MCF10A cells resulted in striking changes in cell shape, leading to mesenchymal cell morphology. The epithelial phenotype could be restored in breast cancer cells by re-expressing Runx1. Analyses of breast tumors and patient data revealed that low Runx1 expression is associated with poor prognosis and decreased survival. We addressed mechanisms for the function of Runx1 in maintaining the epithelial phenotype and find Runx1 directly regulates E-cadherin; and serves as a downstream transcription factor mediating TGFbeta signaling. We also observed through global gene expression profiling of growth factor depleted cells that induction of EMT and loss of Runx1 is associated with activation of TGFbeta and WNT pathways. Thus these findings have identified a novel function for Runx1 in sustaining normal epithelial morphology and preventing EMT and suggest Runx1 levels could be a prognostic indicator of tumor progression
Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition
Runx1 is a well characterized transcription factor essential for hematopoietic differentiation and Runx1 mutations are the cause of leukemias. Runx1 is highly expressed in normal epithelium of most glands and recently has been associated with solid tumors. Notably, the function of Runx1 in the mammary gland and how it is involved in initiation and progression of breast cancer is still unclear. Here we demonstrate the consequences of Runx1 loss in normal mammary epithelial and breast cancer cells. We first observed that Runx1 is decreased in tumorigenic and metastatic breast cancer cells. We also observed loss of Runx1 expression upon induction of epithelial-mesenchymal transition (EMT) in MCF10A (normal-like) cells. Furthermore depletion of Runx1 in MCF10A cells resulted in striking changes in cell shape, leading to mesenchymal cell morphology. The epithelial phenotype could be restored in breast cancer cells by re-expressing Runx1. Analyses of breast tumors and patient data revealed that low Runx1 expression is associated with poor prognosis and decreased survival. We addressed mechanisms for the function of Runx1 in maintaining the epithelial phenotype and find Runx1 directly regulates E-cadherin; and serves as a downstream transcription factor mediating TGFbeta signaling. We also observed through global gene expression profiling of growth factor depleted cells that induction of EMT and loss of Runx1 is associated with activation of TGFbeta and WNT pathways. Thus these findings have identified a novel function for Runx1 in sustaining normal epithelial morphology and preventing EMT and suggest Runx1 levels could be a prognostic indicator of tumor progression
Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer
Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention
Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells
BACKGROUND: Higher-order chromatin structure is often perturbed in cancer and other pathological states. Although several genetic and epigenetic differences have been charted between normal and breast cancer tissues, changes in higher-order chromatin organization during tumorigenesis have not been fully explored. To probe the differences in higher-order chromatin structure between mammary epithelial and breast cancer cells, we performed Hi-C analysis on MCF-10A mammary epithelial and MCF-7 breast cancer cell lines.
RESULTS: Our studies reveal that the small, gene-rich chromosomes chr16 through chr22 in the MCF-7 breast cancer genome display decreased interaction frequency with each other compared to the inter-chromosomal interaction frequency in the MCF-10A epithelial cells. Interestingly, this finding is associated with a higher occurrence of open compartments on chr16-22 in MCF-7 cells. Pathway analysis of the MCF-7 up-regulated genes located in altered compartment regions on chr16-22 reveals pathways related to repression of WNT signaling. There are also differences in intra-chromosomal interactions between the cell lines; telomeric and sub-telomeric regions in the MCF-10A cells display more frequent interactions than are observed in the MCF-7 cells.
CONCLUSIONS: We show evidence of an intricate relationship between chromosomal organization and gene expression between epithelial and breast cancer cells. Importantly, this work provides a genome-wide view of higher-order chromatin dynamics and a resource for studying higher-order chromatin interactions in two cell lines commonly used to study the progression of breast cancer
Search for Matter-Dependent Atmospheric Neutrino Oscillations in Super-Kamiokande
We consider muon neutrino to tau neutrino oscillations in the context of the
Mass Varying Neutrino (MaVaN) model, where the neutrino mass can vary depending
on the electron density along the flight path of the neutrino. Our analysis
assumes a mechanism with dependence only upon the electron density, hence
ordinary matter density, of the medium through which the neutrino travels.
Fully-contained, partially-contained and upward-going muon atmospheric neutrino
data from the Super--Kamiokande detector, taken from the entire SK--I period of
1489 live days, are compared to MaVaN model predictions. We find that, for the
case of 2-flavor oscillations, and for the specific models tested, oscillation
independent of electron density is favored over density dependence. Assuming
maximal mixing, the best-fit case and the density-independent case do not
differ significantly.Comment: 6 pages, 1 figur
Search for Neutral Q-balls in Super-Kamiokande II
A search for Q-balls induced groups of successive contained events has been
carried out in Super-Kamiokande II with 541.7 days of live time.
Neutral Q-balls would emit pions when colliding with nuclei, generating a
signal of successive contained pion events along a track. No candidate for
successive contained event groups has been found in Super-Kamiokande II, so
upper limits on the possible flux of such Q-balls have been obtained.Comment: 5 pages, 5 figures, Submitted to Phys. Lett.
A Measurement of Atmospheric Neutrino Flux Consistent with Tau Neutrino Appearance
A search for the appearance of tau neutrinos from \mutau oscillations in the
atmospheric neutrinos has been performed using 1489.2 days of atmospheric
neutrino data from the Super-Kamiokande-I experiment. A best fit tau neutrino
appearance signal of 138 48 (stat.) (sys.) events is
obtained with an expectation of 78 26 (sys.). The hypothesis of no tau
neutrino appearance is disfavored by 2.4 sigma.Comment: 5 pages, 3 figures, 3 tables, submitted to PR
Solar neutrino measurements in Super-Kamiokande-II
The results of the second phase of the Super-Kamiokande solar neutrino
measurement are presented and compared to the first phase. The solar neutrino
flux spectrum and time-variation as well as oscillation results are
statistically consistent with the first phase and do not show spectral
distortion. The time-dependent flux measurement of the combined first and
second phases coincides with the full period of solar cycle 23 and shows no
correlation with solar activity. The measured boron 8 total flux is 2.38
+/-0.05(stat.) +0.16-0.15(sys.) X 10^6 cm^-2 sec^-1 and the day-night
difference is found to be -6.3 +/-4.2(stat.) +/-3.7(sys.) %. There is no
evidence of systematic tendencies between the first and second phases
The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe
The preponderance of matter over antimatter in the early Universe, the
dynamics of the supernova bursts that produced the heavy elements necessary for
life and whether protons eventually decay --- these mysteries at the forefront
of particle physics and astrophysics are key to understanding the early
evolution of our Universe, its current state and its eventual fate. The
Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed
plan for a world-class experiment dedicated to addressing these questions. LBNE
is conceived around three central components: (1) a new, high-intensity
neutrino source generated from a megawatt-class proton accelerator at Fermi
National Accelerator Laboratory, (2) a near neutrino detector just downstream
of the source, and (3) a massive liquid argon time-projection chamber deployed
as a far detector deep underground at the Sanford Underground Research
Facility. This facility, located at the site of the former Homestake Mine in
Lead, South Dakota, is approximately 1,300 km from the neutrino source at
Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino
charge-parity symmetry violation and mass ordering effects. This ambitious yet
cost-effective design incorporates scalability and flexibility and can
accommodate a variety of upgrades and contributions. With its exceptional
combination of experimental configuration, technical capabilities, and
potential for transformative discoveries, LBNE promises to be a vital facility
for the field of particle physics worldwide, providing physicists from around
the globe with opportunities to collaborate in a twenty to thirty year program
of exciting science. In this document we provide a comprehensive overview of
LBNE's scientific objectives, its place in the landscape of neutrino physics
worldwide, the technologies it will incorporate and the capabilities it will
possess.Comment: Major update of previous version. This is the reference document for
LBNE science program and current status. Chapters 1, 3, and 9 provide a
comprehensive overview of LBNE's scientific objectives, its place in the
landscape of neutrino physics worldwide, the technologies it will incorporate
and the capabilities it will possess. 288 pages, 116 figure
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