Disease Progression Mediated by Egr-1 Associated Signaling in Response to Oxidative Stress

When cellular reducing enzymes fail to shield the cell from increased amounts of reactive oxygen species (ROS), oxidative stress arises. The redox state is misbalanced, DNA and proteins are damaged and cellular transcription networks are activated. This condition can lead to the initiation and/or to the progression of atherosclerosis, tumors or pulmonary hypertension; diseases that are decisively furthered by the presence of oxidizing agents. Redox sensitive genes, like the zinc finger transcription factor early growth response 1 (Egr-1), play a pivotal role in the pathophysiology of these diseases. Apart from inducing apoptosis, signaling partners like the MEK/ERK pathway or the protein kinase C (PKC) can activate salvage programs such as cell proliferation that do not ameliorate, but rather worsen their outcome. Here, we review the currently available data on Egr-1 related signal transduction cascades in response to oxidative stress in the progression of epidemiologically significant diseases. Knowing the molecular pathways behind the pathology will greatly enhance our ability to identify possible targets for the development of new therapeutic strategies

Extracellular Matrix Heterogeneity Regulates Three-Dimensional Morphologies of Breast Adenocarcinoma Cell Invasion

Plasticity and reciprocity of breast cancer cells to various extracellular matrice (ECMs) are three-dimensionally analyzed in quantitative way in a novel and powerful microfluidic in vitro platform. This successfully demonstrates the metastatic potential of cancer cells and their effective strategies of ECM proteolytic remodeling and morphological change, while interacting with other cells and invading into heterogeneous ECMs.International Research & Development Program (Grant 2009-00631)National Research Foundation of Korea (Basic Science Research Program Grant 2012-022481

Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomas

This article is available open access through the publisher’s website. Copyright @ 2009 The Authors.Background - Clusterin expression in various types of human cancers may be higher or lower than in normal tissue, and clusterin may promote or inhibit apoptosis, cell motility, and inflammation. We investigated the role of clusterin in tumor development in mouse models of neuroblastoma. Methods - We assessed expression of microRNAs in the miR-17-92 cluster by real-time reverse transcription–polymerase chain reaction in MYCN-transfected SH-SY5Y and SH-EP cells and inhibited expression by transfection with microRNA antisense oligonucleotides. Tumor development was studied in mice (n = 66) that were heterozygous or homozygous for the MYCN transgene and/or for the clusterin gene; these mice were from a cross between MYCN-transgenic mice, which develop neuroblastoma, and clusterin-knockout mice. Tumor growth and metastasis were studied in immunodeficient mice that were injected with human neuroblastoma cells that had enhanced (by clusterin transfection, four mice per group) or reduced (by clusterin short hairpin RNA [shRNA] transfection, eight mice per group) clusterin expression. All statistical tests were two-sided. Results - Clusterin expression increased when expression of MYCN-induced miR-17-92 microRNA cluster in SH-SY5Y neuroblastoma cells was inhibited by transfection with antisense oligonucleotides compared with scrambled oligonucleotides. Statistically significantly more neuroblastoma-bearing MYCN-transgenic mice were found in groups with zero or one clusterin allele than in those with two clusterin alleles (eg, 12 tumor-bearing mice in the zero-allele group vs three in the two-allele group, n = 22 mice per group; relative risk for neuroblastoma development = 4.85, 95% confidence interval [CI] = 1.69 to 14.00; P = .005). Five weeks after injection, fewer clusterin-overexpressing LA-N-5 human neuroblastoma cells than control cells were found in mouse liver or bone marrow, but statistically significantly more clusterin shRNA-transfected HTLA230 cells (3.27%, with decreased clusterin expression) than control-transfected cells (1.53%) were found in the bone marrow (difference = 1.74%, 95% CI = 0.24% to 3.24%, P = .026). Conclusions - We report, to our knowledge, the first genetic evidence that clusterin is a tumor and metastasis suppressor gene.Sport Aiding Medical Research for Kids (SPARKS), Great Ormond Street Hospital/National Health Service, the National Cancer Institute and University of Parma

Clinical Characteristics of Breast Cancers in African‐American Women with Benign Breast Disease: A Comparison to the Surveillance, Epidemiology, and End Results Program

Benign breast disease ( BBD ) is a very common condition, diagnosed in approximately half of all A merican women throughout their lifecourse. White women with BBD are known to be at substantially increased risk of subsequent breast cancer; however, nothing is known about breast cancer characteristics that develop after a BBD diagnosis in A frican‐ A merican women. Here, we compared 109 breast cancers that developed in a population of A frican‐ A merican women with a history of BBD to 10,601 breast cancers that developed in a general population of A frican‐ A merican women whose cancers were recorded by the M etropolitan D etroit C ancer S urveillance S ystem ( MDCSS population). Demographic and clinical characteristics of the BBD population were compared to the MDCSS population, using chi‐squared tests, F isher's exact tests, t ‐tests, and W ilcoxon tests where appropriate. K aplan– M eier curves and Cox regression models were used to examine survival. Women in the BBD population were diagnosed with lower grade (p = 0.02), earlier stage cancers (p = 0.003) that were more likely to be hormone receptor‐positive (p = 0.03) compared to the general metropolitan Detroit A frican‐ A merican population. In situ cancers were more common among women in the BBD cohort (36.7%) compared to the MDCSS population (22.1%, p < 0.001). Overall, women in the BBD population were less likely to die from breast cancer after 10 years of follow‐up (p = 0.05), but this association was not seen when analyses were limited to invasive breast cancers. These results suggest that breast cancers occurring after a BBD diagnosis may have more favorable clinical parameters, but the majority of cancers are still invasive, with survival rates similar to the general A frican‐ A merican population.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109284/1/tbj12331.pd

Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle.

Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration through custom-etched pores yields the same damage threshold, with ∼4-µm pores causing intermediate levels of both damage and cell cycle suppression. High curvature imposed rapidly by pores or probes or else by small micronuclei consistently associates nuclear rupture with dilution of stiff lamin-B filaments, loss of repair factors, and entry from cytoplasm of chromatin-binding cGAS (cyclic GMP-AMP synthase). The cell cycle block caused by constricted migration is nonetheless reversible, with a potential for DNA misrepair and genome variation

Lung Cancer in Pulmonary Fibrosis: Tales of Epithelial Cell Plasticity

Lung epithelial cells exhibit a high degree of plasticity. Alterations to lung epithelial cell function are critically involved in several chronic lung diseases such as pulmonary fibrosis. Pulmonary fibrosis is characterized by repetitive injury and subsequent impaired repair of epithelial cells, which leads to aberrant growth factor activation and fibroblast accumulation. Increased proliferation and hyper- and metaplasia of epithelial cells upon injury have also been observed in pulmonary fibrosis; this epithelial cell activation might represent the basis for lung cancer development. Indeed, several studies have provided histopathological evidence of an increased incidence of lung cancer in pulmonary fibrosis. The mechanisms involved in the development of cancer in pulmonary fibrosis, however, remain poorly understood. This review highlights recently uncovered molecular mechanisms shared between lung cancer and fibrosis, which extend the current evidence of a common trait of cancer and fibrosis, as provided by histopathological observations. Copyright (C) 2011 S. Karger AG, Base