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Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell-selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes.

BackgroundPulmonary hypertension (PH) in patients with bronchopulmonary dysplasia (BPD) results from vasoconstriction and/or vascular remodeling, which can be regulated by mitogen-activated protein kinases (MAPKs). MAPKs are deactivated by dual-specificity phosphatases (DUSPs). We hypothesized that single-nucleotide polymorphisms (SNPs) in DUSP genes could be used to predict PH in BPD.MethodsPreterm infants diagnosed with BPD (n = 188) were studied. PH was defined by echocardiographic criteria. Genomic DNA isolated from patient blood samples was analyzed for 31 SNPs in DUSP genes. Clinical characteristics and minor allele frequencies were compared between BPD-PH (cases) and BPD-without PH (control) groups. Biomarker models to predict PH in BPD using clinical and SNP data were tested by calculations of area under the ROC curve.ResultsIn our BPD cohort, 32% (n = 61) had PH. Of the DUSP SNPs evaluated, DUSP1 SNP rs322351 was less common, and DUSP5 SNPs rs1042606 and rs3793892 were more common in cases than in controls. The best fit biomarker model combines clinical and DUSP genetic data with an area under the ROC curve of 0.76.ConclusionWe identified three DUSP SNPs as potential BPD-PH biomarkers. Combining clinical and DUSP genetic data yields the most robust predictor for PH in BPD.

Identified over a dozen years ago in the brain and pancreatic islet, β IV-spectrin is critical for the local organization of protein complexes throughout the nervous system. β IV-Spectrin targets ion channels and adapter proteins to axon initial segments and nodes of Ranvier in neurons, and β IV-spectrin dysfunction underlies ataxia and early death in mice. Despite advances in β IV-spectrin research in the nervous system, its role in pancreatic islet biology is unknown. Here, we report that β IV-spectrin serves as a multifunctional structural and signaling platform in the pancreatic islet. We report that β IV-spectrin directly associates with and targets the calcium/calmodulin-dependent protein kinase II (CaMKII) in pancreatic islets. In parallel, β IV-spectrin targets ankyrin-B and the ATP-sensitive potassium channel. Consistent with these findings, β IV-spectrin mutant mice lacking CaMKII- or ankyrin-binding motifs display selective loss of expression and targeting of key protein components, including CaMKIIδ. β IV-Spectrin–targeted CaMKII directly phosphorylates the inwardly-rectifying potassium channel, Kir6.2 (alpha subunit of K ATP channel complex), and we identify the specific residue, Kir6.2 T224, responsible for CaMKII-dependent regulation of K ATP channel function. CaMKII-dependent phosphorylation alters channel regulation resulting in K ATP channel inhibition, a cellular phenotype consistent with aberrant insulin regulation. Finally, we demonstrate aberrant K ATP channel phosphorylation in β IV-spectrin mutant mice. In summary, our findings establish a broader role for β IV-spectrin in regulation of cell membrane excitability in the pancreatic islet, define the pathway for CaMKII local control in pancreatic beta cells, and identify the mechanism for CaMKII-dependent regulation of K ATP channels.

The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis Dan Li 1 , Xin Yin 1 , Erik J. Zmuda 1 , 2 , Christopher C. Wolford 1 , 3 , Xiaocheng Dong 4 , Morris F. White 4 , 5 and Tsonwin Hai 1 , 2 , 3 1 Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, the Ohio State Biochemistry Program, Ohio State University, Columbus, Ohio 2 Molecular, Cellular and Developmental Biology Program, Ohio State University, Columbus, Ohio 3 Integrated Biomedical Graduate Program, Ohio State University, Columbus, Ohio 4 Children's Hospital, Harvard Medical School, Boston, Massachusetts 5 Howard Hughes Medical Institute, Boston, Massachusetts Address correspondence and reprint requests to Tsonwin Hai, Room 174 Rightmire Hall, 1060 Carmack Rd., Ohio State University, Columbus, OH 43210. E-mail: hai.2{at}osu.edu Abstract OBJECTIVE —β-Cell failure is an essential component of all types of diabetes, and the insulin receptor substrate 2 (IRS2) branch of signaling plays a key role in β-cell survival and function. We tested the hypothesis that activating transcription factor 3 (ATF3), a stress-inducible proapoptotic gene, downregulates the expression of IRS2 in β-cells. RESEARCH DESIGN AND METHODS —We used both the gain- and loss-of-function approaches to test the effects of ATF3 on IRS2 gene expression. We also analyzed the binding of ATF3 to the IRS2 promoter by chromatin immunoprecipitation assay and the transcription of the IRS2 gene by polymerase II occupancy assay. Furthermore, we tested the ability of IRS2 to alleviate the proapoptotic effects of ATF3 in cultured β-cells and in transgenic mice using the rat insulin promoter to drive the transgenes. RESULTS —Expression of ATF3 is sufficient to reduce IRS2 gene expression; in contrast, knockdown or knockout of ATF3 reduces the ability of stress signals to downregulate IRS2 expression. ATF3 binds to the IRS2 promoter in vivo, and the binding of ATF3 correlates with decreased IRS2 gene transcription. Functionally, expression of IRS2 protects β-cells from ATF3-induced apoptosis. CONCLUSIONS —IRS2 is a target gene of ATF3, and its repression by ATF3 contributes, at least partly, to the apoptosis induced by ATF3. Because ATF3 is a stress-inducible gene, our work provides a direct link to explain how environmental stress factors can modulate IRS2 gene transcription. ATF3, activating transcription factor 3 ChIP, chromatin immunoprecipitation CREB, cAMP response element-binding protein FACS, fluorescence-activated cell sorting GLP, glucagon-like peptide IFN-γ, γ-interferon IL-1β, interleukin-1β IRS2, insulin receptor substrate 2 MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium RIP, rat insulin promoter TNF-α, tumor necrosis factor-α Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 5 December 2007. DOI: 10.2337/db07-0717. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0717 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received May 28, 2007. Accepted November 20, 2007. DIABETES

The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined. Increasing glucose (5-25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β. Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target.

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes ( TP53 , PIK3CA and GATA3 ) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3 , PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer. The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes ( TP53 , PIK3CA and GATA3 ) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified. Gene variation in breast cancer This Article from the Cancer Genome Atlas consortium describes a multifaceted analysis of primary breast cancers in 825 people. Exome sequencing, copy number variation, DNA methylation, messenger RNA arrays, microRNA sequencing and proteomic analyses were performed and integrated to shed light on breast-cancer heterogeneity. Just three genes — TP53 , PIK3CA and GATA3 — are mutated at greater than 10% frequency across all breast cancers. Many subtype-associated and novel mutations were identified, as well as two breast-cancer subgroups with specific signalling-pathway signatures. The analyses also suggest that much of the clinically observable plasticity and heterogeneity occurs within, and not across, the major subtypes of breast cancer.

Chronic intake of saturated free fatty acids is associated with diabetes and may contribute to the impairment of functional beta cell mass. Mitogen activated protein kinase 8 interacting protein 1 also called islet brain 1 (IB1) is a candidate gene for diabetes that is required for beta cell survival and glucose-induced insulin secretion (GSIS). In this study we investigated whether IB1 expression is required for preserving beta cell survival and function in response to palmitate. Chronic exposure of MIN6 and isolated rat islets cells to palmitate led to reduction of the IB1 mRNA and protein content. Diminution of IB1 mRNA and protein level relied on the inducible cAMP early repressor activity and proteasome-mediated degradation, respectively. Suppression of IB1 level mimicked the harmful effects of palmitate on the beta cell survival and GSIS. Conversely, ectopic expression of IB1 counteracted the deleterious effects of palmitate on the beta cell survival and insulin secretion. These findings highlight the importance in preserving the IB1 content for protecting beta cell against lipotoxicity in diabetes.

Biomedical research relies on available biomaterials and associated data, and the quality of this starting material can have a significant impact on the quality of the experimental results. In the 2000s, best-practice documents and guidelines for biorepositories were published, followed in the 2010s by standards documents used to support accreditation. The College of American Pathologists Biorepository Accreditation Program and the International Standards Organization's standard 20387 were launched in 2012 and 2018, respectively. To identify quantitative and qualitative differences between the 2 aforementioned biorepository accreditation standards for use by the larger biomedical research community; the results will empower biorepositories to select an accreditation program that best fits their goals. Individual requirements of both accreditation standards were identified and a bidirectional crosswalk was performed to identify gaps. Requirements were assigned to one of several standardized categories to enable comparison of the relative emphasis of different categories between the standards. Quantitatively, the College of American Pathologists program is comprehensive and stands alone, with 523 requirements, whereas the International Standards Organization program contains 167 requirements and is comprehensive through its incorporation and reference to numerous related standards documents. Qualitatively, both programs rely heavily on the implementation of an overarching quality management system and both programs can accommodate different types of biobanks (eg, human and animal). The standards differ in number of requirements, distribution of requirements across categories, and amount of reliance on separate standard documents. This information may aid in selection of an appropriate accreditation standard.

Biomedical research relies on available biomaterials and associated data, and the quality of this starting material can have a significant impact on the quality of the experimental results. In the 2000s, best-practice documents and guidelines for biorepositories were published, followed in the 2010s by standards documents used to support accreditation. The College of American Pathologists Biorepository Accreditation Program and the International Standards Organization's standard 20387 were launched in 2012 and 2018, respectively.CONTEXT.—Biomedical research relies on available biomaterials and associated data, and the quality of this starting material can have a significant impact on the quality of the experimental results. In the 2000s, best-practice documents and guidelines for biorepositories were published, followed in the 2010s by standards documents used to support accreditation. The College of American Pathologists Biorepository Accreditation Program and the International Standards Organization's standard 20387 were launched in 2012 and 2018, respectively.To identify quantitative and qualitative differences between the two aforementioned biorepository accreditation standards for use by the larger biomedical research community; the results will empower biorepositories to select an accreditation program that best fits their goals.OBJECTIVE.—To identify quantitative and qualitative differences between the two aforementioned biorepository accreditation standards for use by the larger biomedical research community; the results will empower biorepositories to select an accreditation program that best fits their goals.Individual requirements of both accreditation standards were identified and a bidirectional crosswalk was performed to identify gaps. Requirements were assigned to one of several standardized categories to enable comparison of the relative emphasis of different categories between the standards.DESIGN.—Individual requirements of both accreditation standards were identified and a bidirectional crosswalk was performed to identify gaps. Requirements were assigned to one of several standardized categories to enable comparison of the relative emphasis of different categories between the standards.Quantitatively, the College of American Pathologists program is comprehensive and stands alone, with 523 requirements, whereas the International Standards Organization program contains 167 requirements and is comprehensive through its incorporation and reference to numerous related standards documents. Qualitatively, both programs rely heavily on the implementation of an overarching quality management system and both programs can accommodate different types of biobanks (eg, human and animal).RESULTS.—Quantitatively, the College of American Pathologists program is comprehensive and stands alone, with 523 requirements, whereas the International Standards Organization program contains 167 requirements and is comprehensive through its incorporation and reference to numerous related standards documents. Qualitatively, both programs rely heavily on the implementation of an overarching quality management system and both programs can accommodate different types of biobanks (eg, human and animal).The standards differ in number of requirements, distribution of requirements across categories, and amount of reliance on separate standard documents. This information may aid in selection of an appropriate accreditation standard.CONCLUSIONS.—The standards differ in number of requirements, distribution of requirements across categories, and amount of reliance on separate standard documents. This information may aid in selection of an appropriate accreditation standard.