Publications by authors named "Hallgeir Rui"

93 Publications

Quantification of spatial tumor heterogeneity in immunohistochemistry staining images.

Bioinformatics 2020 Dec 4. Epub 2020 Dec 4.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI.

Motivation: Quantitative Immunofluorescence (QIF) is often used for immunohistochemistry (IHC) quantification of proteins that serve as cancer biomarkers. Advanced image analysis systems for pathology allow capturing expression levels in each individual cell or subcellular compartment. However, only the Mean Signal Intensity (MSI) within the cancer tissue region of interest is usually considered as biomarker completely ignoring the issue of tumor heterogeneity.

Results: We propose using IHC image-derived information on the spatial distribution of cellular signal intensity (CSI) of protein expression within the cancer cell population to quantify both mean expression level and tumor heterogeneity of CSI levels. We view CSI levels as marks in a marked point process of cancer cells in the tissue and define spatial indices based on conditional mean and conditional variance of the marked point process. The proposed methodology provides objective metrics of cell-to-cell heterogeneity in protein expressions that allow discriminating between different patterns of heterogeneity. The prognostic utility of new spatial indices is investigated and compared to the standard MSI biomarkers using the protein expressions in tissue microarrays (TMAs) incorporating tumor tissues from1000+ breast cancer patients.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa965DOI Listing
December 2020

The membrane-associated form of cyclin D1 enhances cellular invasion.

Oncogenesis 2020 Sep 18;9(9):83. Epub 2020 Sep 18.

Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, 19096, USA.

The essential G-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4 and CDK6 thereby contributing to G-S cell-cycle progression. In addition to the nucleus, herein cyclin D1 was also located in the cytoplasmic membrane. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1) induced transwell migration and the velocity of cellular migration. The cyclin D1 was sufficient to induce G-S cell-cycle progression, cellular proliferation, and colony formation. The cyclin D1 was sufficient to induce phosphorylation of the serine threonine kinase Akt (Ser473) and augmented extranuclear localized 17β-estradiol dendrimer conjugate (EDC)-mediated phosphorylation of Akt (Ser473). These studies suggest distinct subcellular compartments of cell cycle proteins may convey distinct functions.
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http://dx.doi.org/10.1038/s41389-020-00266-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501870PMC
September 2020

Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis.

Oncogene 2020 09 17;39(38):6129-6137. Epub 2020 Aug 17.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Activation of cancer-associated fibroblasts (CAFs) and ensuing desmoplasia play an important role in the growth and progression of solid tumors. Here we demonstrate that, within colon and pancreatic ductal adenocarcinoma tumors, efficient stromagenesis relies on downregulation of the IFNAR1 chain of the type I interferon (IFN1) receptor. Expression of the fibroblast activation protein (FAP) and accumulation of the extracellular matrix (ECM) was notably impaired in tumors grown in the Ifnar1 (SA) knock-in mice, which are deficient in IFNAR1 downregulation. Primary fibroblasts from these mice exhibited elevated levels of Smad7, a negative regulator of the transforming growth factor-β (TGFβ) pathway. Knockdown of Smad7 alleviated deficient ECM production in SA fibroblasts in response to TGFβ. Analysis of human colorectal cancers revealed an inverse correlation between IFNAR1 and FAP levels. Whereas growth of tumors in SA mice was stimulated by co-injection of wild type but not SA fibroblasts, genetic ablation of IFNAR1 in fibroblasts also accelerated tumor growth. We discuss how inactivation of IFNAR1 in CAFs acts to stimulate stromagenesis and tumor growth.
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http://dx.doi.org/10.1038/s41388-020-01424-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502515PMC
September 2020

Individualized multi-omic pathway deviation scores using multiple factor analysis.

Biostatistics 2020 Aug 6. Epub 2020 Aug 6.

Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.

Malignant progression of normal tissue is typically driven by complex networks of somatic changes, including genetic mutations, copy number aberrations, epigenetic changes, and transcriptional reprogramming. To delineate aberrant multi-omic tumor features that correlate with clinical outcomes, we present a novel pathway-centric tool based on the multiple factor analysis framework called padma. Using a multi-omic consensus representation, padma quantifies and characterizes individualized pathway-specific multi-omic deviations and their underlying drivers, with respect to the sampled population. We demonstrate the utility of padma to correlate patient outcomes with complex genetic, epigenetic, and transcriptomic perturbations in clinically actionable pathways in breast and lung cancer.
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http://dx.doi.org/10.1093/biostatistics/kxaa029DOI Listing
August 2020

Malignant cell-specific pro-tumorigenic role of type I interferon receptor in breast cancers.

Cancer Biol Ther 2020 Jul 7;21(7):629-636. Epub 2020 May 7.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.

Within the microenvironment of solid tumors, stress associated with deficit of nutrients and oxygen as well as tumor-derived factors triggers the phosphorylation-dependent degradation of the IFNAR1 chain of type I interferon (IFN1) receptor and ensuing suppression of the IFN1 pathway. Here we sought to examine the importance of these events in malignant mammary cells. Expression of non-degradable IFNAR1 mutant in mouse mammary adenocarcinoma cells stimulated the IFN1 pathway yet did not affect growth of these cells in vitro or ability to form subcutaneous tumors in the syngeneic mice. Remarkably, these cells exhibited a notably accelerated growth when transplanted orthotopically into mammary glands. Importantly, in human patients with either ER+ or ER- breast cancers, high levels of IFNAR1 were associated with poor prognosis. We discuss the putative mechanisms underlying the pro-tumorigenic role of IFNAR1 in malignant breast cells.
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http://dx.doi.org/10.1080/15384047.2020.1750297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515508PMC
July 2020

Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury.

Cancers (Basel) 2020 Apr 16;12(4). Epub 2020 Apr 16.

Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

While radiation therapy (RT) can improve cancer outcomes, it can lead to radiation-induced heart dysfunction (RIHD) in patients with thoracic tumors. This study examines the role of adaptive immune cells in RIHD. In Salt-Sensitive (SS) rats, image-guided whole-heart RT increased cardiac T-cell infiltration. We analyzed the functional requirement for these cells in RIHD using a genetic model of T- and B-cell deficiency (interleukin-2 receptor gamma chain knockout (IL2RG)) and observed a complex role for these cells. Surprisingly, while IL2RG deficiency conferred protection from cardiac hypertrophy, it worsened heart function via echocardiogram three months after a large single RT dose, including increased end-systolic volume (ESV) and reduced ejection fraction (EF) and fractional shortening (FS) ( < 0.05). Fractionated RT, however, did not yield similarly increased injury. Our results indicate that T cells are not uniformly required for RIHD in this model, nor do they account for our previously reported differences in cardiac RT sensitivity between SS and SS.BN3 rats. The increasing use of immunotherapies in conjunction with traditional cancer treatments demands better models to study the interactions between immunity and RT for effective therapy. We present a model that reveals complex roles for adaptive immune cells in cardiac injury that vary depending on clinically relevant factors, including RT dose/fractionation, sex, and genetic background.
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http://dx.doi.org/10.3390/cancers12040983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226421PMC
April 2020

Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer.

Cancers (Basel) 2020 Mar 19;12(3). Epub 2020 Mar 19.

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK 73104, USA.

Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45 immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45 immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both tumor infiltrating T-lymphocytes and tumor associated-macrophages were skewed towards T2 in DOX-treated residual breast tumors; however, ESTA suppressed these changes. This study suggests that DOX treatment instigates intratumoral infiltration of immune cells through E-selectin, and functional blockade of E-selectin may reduce residual tumor burden as well as metastasis through suppression of T2 shift.
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http://dx.doi.org/10.3390/cancers12030725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140021PMC
March 2020

Mapping Mammary Tumor Traits in the Rat.

Methods Mol Biol 2019 ;2018:249-267

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.

For nearly a century, the rat has served as a key model for studying the pathophysiology and genetic risk modifiers of breast cancer. Rat mammary tumors that initiate after exposure to carcinogens or estrogens closely resemble the etiological, histopathological, and genomic features of human breast cancer. Recent developments in genome-editing techniques in the rat have also enabled the development of sophisticated models for identifying the genetic modifiers of the nonmalignant tumor microenvironment that contribute to the formation, progression, and outcome of breast cancer. In this protocol review, we discuss the current methodologies for the three genetic mapping techniques in the rat that are widely used for identifying and testing the heritable genetic modifiers of breast cancer.
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http://dx.doi.org/10.1007/978-1-4939-9581-3_12DOI Listing
November 2019

The p52 isoform of SHC1 is a key driver of breast cancer initiation.

Breast Cancer Res 2019 06 15;21(1):74. Epub 2019 Jun 15.

Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Background: SHC1 proteins (also called SHCA) exist in three functionally distinct isoforms (p46SHC, p52SHC, and p66SHC) that serve as intracellular adaptors for several key signaling pathways in breast cancer. Despite the broad evidence implicating SHC1 gene products as a central mediator of breast cancer, testing the isoform-specific roles of SHC1 proteins have been inaccessible due to the lack of isoform-specific inhibitors or gene knockout models.

Methods: Here, we addressed this issue by generating the first isoform-specific gene knockout models for p52SHC and p66SHC, using germline gene editing in the salt-sensitive rat strain. Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. Rats were dosed with 7,12-dimethylbenz(a)anthracene (DMBA) by oral gavage to induce mammary tumors, and progression of tumor development was followed for 15 weeks. At 15 weeks, tumors were excised and analyzed by RNA-seq to determine differences between tumors lacking p66SHC or p52SHC.

Results: Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. These data, combined with p52SHC being the predominant isoform that is upregulated in human and rat tumors, provide the first evidence that p52SHC is the oncogenic isoform of Shc1 gene products in breast cancer. Compared with WT tumors, 893 differentially expressed (DE; FDR < 0.05) genes were detected in p52SHC KO tumors compared with only 18 DE genes in the p66SHC KO tumors, further highlighting that p52SHC is the relevant SHC1 isoform in breast cancer. Finally, gene network analysis revealed that p52SHC KO disrupted multiple key pathways that have been previously implicated in breast cancer initiation and progression, including ESR1 and mTORC2/RICTOR.

Conclusion: Collectively, these data demonstrate the p52SHC isoform is the key driver of DMBA-induced breast cancer while the expression of p66SHC and p46SHC are not enough to compensate.
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http://dx.doi.org/10.1186/s13058-019-1155-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570928PMC
June 2019

Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome.

Breast Cancer Res Treat 2019 Aug 4;177(1):77-91. Epub 2019 Jun 4.

Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA.

Purpose: Understanding the molecular mediators of breast cancer survival is critical for accurate disease prognosis and improving therapies. Here, we identified Neuronatin (NNAT) as a novel antiproliferative modifier of estrogen receptor-alpha (ER+) breast cancer.

Experimental Design: Genomic regions harboring breast cancer modifiers were identified by congenic mapping in a rat model of carcinogen-induced mammary cancer. Tumors from susceptible and resistant congenics were analyzed by RNAseq to identify candidate genes. Candidates were prioritized by correlation with outcome, using a consensus of three breast cancer patient cohorts. NNAT was transgenically expressed in ER+ breast cancer lines (T47D and ZR75), followed by transcriptomic and phenotypic characterization.

Results: We identified a region on rat chromosome 3 (142-178 Mb) that modified mammary tumor incidence. RNAseq of the mammary tumors narrowed the candidate list to three differentially expressed genes: NNAT, SLC35C2, and FAM210B. NNAT mRNA and protein also correlated with survival in human breast cancer patients. Quantitative immunohistochemistry of NNAT protein revealed an inverse correlation with survival in a univariate analysis of patients with invasive ER+ breast cancer (training cohort: n = 444, HR = 0.62, p = 0.031; validation cohort: n = 430, HR = 0.48, p = 0.004). NNAT also held up as an independent predictor of survival after multivariable adjustment (HR = 0.64, p = 0.038). NNAT significantly reduced proliferation and migration of ER+ breast cancer cells, which coincided with altered expression of multiple related pathways.

Conclusions: Collectively, these data implicate NNAT as a novel mediator of cell proliferation and migration, which correlates with decreased tumorigenic potential and prolonged patient survival.
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http://dx.doi.org/10.1007/s10549-019-05307-8DOI Listing
August 2019

Identification of a Rat Mammary Tumor Risk Locus That Is Syntenic with the Commonly Amplified 8q12.1 and 8q22.1 Regions in Human Breast Cancer Patients.

G3 (Bethesda) 2019 05 7;9(5):1739-1743. Epub 2019 May 7.

Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI

Breast cancer risk is 31% heritable, yet the majority of the underlying risk factors remain poorly defined. Here, we used F2-linkage analysis in a rat mammary tumor model to identify a novel 11.2 Mb modifier locus of tumor incidence and burden on rat chromosome 5 (chr5: 15.4 - 26.6 Mb). Genomic and RNA sequencing analysis identified four differentially expressed candidates: , , , and Analysis of the human syntenic candidate region revealed that is in close proximity to a previously reported genetic risk locus for human breast cancer. Moreover, analysis of the candidate genes in The Cancer Genome Atlas (TCGA) revealed that they fall within the commonly amplified 8q12.1 and 8q22.1 regions in human breast cancer patients and are correlated with worse overall survival. Collectively, this study presents novel evidence suggesting that , , , and are potential modifiers of human breast cancer risk and outcome.
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http://dx.doi.org/10.1534/g3.118.200873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505137PMC
May 2019

Mapping genetic modifiers of radiation-induced cardiotoxicity to rat chromosome 3.

Am J Physiol Heart Circ Physiol 2019 06 8;316(6):H1267-H1280. Epub 2019 Mar 8.

Department of Radiation Oncology, Medical College of Wisconsin , Milwaukee, Wisconsin.

Radiation therapy is used in ~50% of cancer patients to reduce the risk of recurrence and in some cases improve survival. Despite these benefits, doses can be limited by toxicity in multiple organs, including the heart. The underlying causes and biomarkers of radiation-induced cardiotoxicity are currently unknown, prompting the need for experimental models with inherent differences in sensitivity and resistance to the development of radiation-induced cardiotoxicity. We have identified the parental SS (Dahl salt-sensitive/Mcwi) rat strain to be a highly-sensitized model of radiation-induced cardiotoxicity. In comparison, substitution of rat chromosome 3 from the resistant BN (Brown Norway) rat strain onto the SS background (SS-3 consomic) significantly attenuated radiation-induced cardiotoxicity. SS-3 rats had less radiation-induced cardiotoxicity than SS rats, as measured by survival, pleural and pericardial effusions, echocardiogram parameters, and histological damage. Mast cells, previously shown to have predominantly protective roles in radiation-induced cardiotoxicity, were increased in the more resistant SS-3 hearts postradiation. RNA sequencing from SS and SS-3 hearts at 1 wk postradiation revealed 5,098 differentially expressed candidate genes across the transcriptome and 350 differentially expressed genes on rat chromosome 3, which coincided with enrichment of multiple pathways, including mitochondrial dysfunction, sirtuin signaling, and ubiquitination. Upstream regulators of enriched pathways included the oxidative stress modulating transcription factor, , which is located on rat chromosome 3. target genes were also differentially expressed in the SS vs. SS-3 consomic hearts postradiation. Collectively, these data confirm the existence of heritable modifiers in radiation-induced cardiotoxicity and provide multiple biomarkers, pathways, and candidate genes for future analyses. This novel study reveals that heritable genetic factors have the potential to modify normal tissue sensitivity to radiation. Gene variant(s) on rat chromosome 3 can contribute to enhanced cardiotoxicity displayed in the SS rats vs. the BN and SS-3 consomic rats. Identifying genes that lead to understanding the mechanisms of radiation-induced cardiotoxicity represents a novel method to personalize radiation treatment, as well as predict the development of radiation-induced cardiotoxicity.
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http://dx.doi.org/10.1152/ajpheart.00482.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620678PMC
June 2019

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.

Cancer Cell 2019 01;35(1):33-45.e6

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy.
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http://dx.doi.org/10.1016/j.ccell.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336114PMC
January 2019

Exploring drivers of gene expression in the Cancer Genome Atlas.

Bioinformatics 2019 01;35(1):62-68

Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.

Motivation: The Cancer Genome Atlas (TCGA) has greatly advanced cancer research by generating, curating and publicly releasing deeply measured molecular data from thousands of tumor samples. In particular, gene expression measures, both within and across cancer types, have been used to determine the genes and proteins that are active in tumor cells.

Results: To more thoroughly investigate the behavior of gene expression in TCGA tumor samples, we introduce a statistical framework for partitioning the variation in gene expression due to a variety of molecular variables including somatic mutations, transcription factors (TFs), microRNAs, copy number alternations, methylation and germ-line genetic variation. As proof-of-principle, we identify and validate specific TFs that influence the expression of PTPN14 in breast cancer cells.

Availability And Implementation: We provide a freely available, user-friendly, browseable interactive web-based application for exploring the results of our transcriptome-wide analyses across 17 different cancers in TCGA at http://ls-shiny-prod.uwm.edu/edge_in_tcga. All TCGA Open Access tier data are available at the Broad Institute GDAC Firehose and were downloaded using the TCGA2STAT R package. TCGA Controlled Access tier data are available via controlled access through the Genomic Data Commons (GDC). R scripts used to download, format and analyze the data and produce the interactive R/Shiny web app have been made available on GitHub at https://github.com/andreamrau/EDGE-in-TCGA.
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http://dx.doi.org/10.1093/bioinformatics/bty551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298045PMC
January 2019

Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells.

Proc Natl Acad Sci U S A 2018 10 17;115(40):E9298-E9307. Epub 2018 Sep 17.

Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107;

Overexpression of the deubiquitylase ubiquitin-specific peptidase 22 (USP22) is a marker of aggressive cancer phenotypes like metastasis, therapy resistance, and poor survival. Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional cofactor complex. Challenging the dogma, we report here a nontranscriptional role for USP22 via a direct effect on the core cell cycle machinery: that is, the deubiquitylation of the G1 cyclin D1 (CCND1). Deubiquitylation by USP22 protects CCND1 from proteasome-mediated degradation and occurs separately from the canonical phosphorylation/ubiquitylation mechanism previously shown to regulate CCND1 stability. We demonstrate that control of CCND1 is a key mechanism by which USP22 mediates its known role in cell cycle progression. Finally, USP22 and CCND1 levels correlate in patient lung and colorectal cancer samples and our preclinical studies indicate that targeting USP22 in combination with CDK inhibitors may offer an approach for treating cancer patients whose tumors exhibit elevated CCND1.
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http://dx.doi.org/10.1073/pnas.1807704115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176615PMC
October 2018

Loss of Nuclear Localized Parathyroid Hormone-Related Protein in Primary Breast Cancer Predicts Poor Clinical Outcome and Correlates with Suppressed Stat5 Signaling.

Clin Cancer Res 2018 12 10;24(24):6355-6366. Epub 2018 Aug 10.

Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Purpose: Parathyroid hormone-related protein (PTHrP) is required for normal mammary gland development and biology. A gene polymorphism is associated with breast cancer risk, and PTHrP promotes growth of osteolytic breast cancer bone metastases. Accordingly, current dogma holds that PTHrP is upregulated in malignant primary breast tumors, but solid evidence for this assumption is missing.

Experimental Design: We used quantitative IHC to measure PTHrP in normal and malignant breast epithelia, and correlated PTHrP levels in primary breast cancer with clinical outcome.

Results: PTHrP levels were markedly downregulated in malignant compared with normal breast epithelia. Moreover, low levels of nuclear localized PTHrP in cancer cells correlated with unfavorable clinical outcome in a test and a validation cohort of breast cancer treated at different institutions totaling nearly 800 cases. PTHrP mRNA levels in tumors of a third cohort of 737 patients corroborated this association, also after multivariable adjustment for standard clinicopathologic parameters. Breast cancer PTHrP levels correlated strongly with transcription factors Stat5a/b, which are established markers of favorable prognosis and key mediators of prolactin signaling. Prolactin stimulated PTHrP transcript and protein in breast cancer cell lines and , effects mediated by Stat5 through the P2 gene promoter, producing transcript AT6 encoding the PTHrP 1-173 isoform. Low levels of AT6, but not two alternative transcripts, correlated with poor clinical outcome.

Conclusions: This study overturns the prevailing view that PTHrP is upregulated in primary breast cancers and identifies a direct prolactin-Stat5-PTHrP axis that is progressively lost in more aggressive tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3280DOI Listing
December 2018

CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion.

Cancer Res 2018 04 22;78(7):1657-1671. Epub 2018 Jan 22.

Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania.

The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5 breast cancer epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response-based treatments, allowing a dose reduction of standard chemotherapy and radiation. This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331183PMC
April 2018

Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth.

Oncotarget 2017 Oct 4;8(47):81754-81775. Epub 2017 Aug 4.

Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA.

The gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased >30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1) , enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1 had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80 and CD11b macrophages and increasing angiogenesis. Cyclin D1 induced secretion of factors that promoted expansion of stem cells (breast stem-like cells, embryonic stem cells and bone marrow derived stem cells). Cyclin D1 resulted in increased secretion of proinflammatory cytokines (CCL2, CCL7, CCL11, CXCL1, CXCL5, CXCL9, CXCL12), CSF (CSF1, GM-CSF1) and osteopontin (OPN) (30-fold). OPN was induced by cyclin D1 in fibroblasts, breast epithelial cells and in the murine transgenic mammary gland and OPN was sufficient to induce stem cell expansion. These results demonstrate that cyclin D1 drives tumor microenvironment heterocellular signaling, promoting several key hallmarks of cancer.
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http://dx.doi.org/10.18632/oncotarget.19953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669846PMC
October 2017

Comparative Survival Analysis of Invasive Breast Cancer Patients Treated by a U.S. Military Medical Center and Matched Patients From the U.S. General Population.

Mil Med 2017 11;182(11):e1851-e1858

Chan Soon-Shiong Institute of Molecular Medicine at Windber, 620 Seventh Street, Windber, PA 15963.

Objective: Many differences between U.S. military beneficiaries and the U.S. general population, including differences in health care access, are known factors affecting invasive breast cancer outcomes. Thus, comparing the two populations for any outcome differences and their contributing factors may provide insights to breast cancer prognosis.

Methods: Using a marginal Cox proportional hazards regression model, we compared disease-specific survival (DSS) and 5-year DSS rates between 418 patients from the Clinical Breast Care Project at the Walter Reed National Military Medical Center (CBCP-WR) and a set of 1:5 randomly matched patients from the Surveillance, Epidemiology, and End Results program. Patients were compared in the "demographic model" (adjusted by diagnosis year, age, and race) and the "overall model" (further adjusted by estrogen receptor, progesterone receptor, stage, and grade).

Results: In the "overall model," CBCP-WR patients were less likely overall to die from breast cancer (hazard ratio [HR] = 0.631, 95% confidence interval [CI] = 0.437-0.911; p = 0.014). This increase in survival was also significant in African American patients (HR = 0.524, 95% CI = 0.277-0.992; p = 0.047) and patients older than 50 (HR = 0.511, 95% CI = 0.306-0.854; p = 0.010). The advantage in 5-year DSS rate for CBCP-WR patients was 5.3% (93.1% vs. 87.8%; p < 0.001) in the "demographic model" and 3.4% (91.3% vs. 87.9%; p = 0.018) in the "overall model."

Conclusion: CBCP-WR patients demonstrated significantly better DSS over matched SEER patients. Although a portion of the outcome disparity, i.e., 36% of the 5.3% DSS rate difference, could be explained by differences in tumor characteristics, the cause(s) behind the majority of the disparity has yet to be identified. Identification and further analysis of contributing factors to survival differences have the potential to improve clinical practice and outcomes for invasive breast cancer patients.
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http://dx.doi.org/10.7205/MILMED-D-17-00097DOI Listing
November 2017

Pathologic evaluation of tumor-associated macrophage density and vessel inflammation in invasive breast carcinomas.

Oncol Lett 2017 Aug 22;14(2):2111-2118. Epub 2017 Jun 22.

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Tumor-associated macrophages (TAMs) are major constituents of the tumor microenvironment in solid tumors and have been implicated as mediators of tumor progression, invasion and metastasis. Correspondingly, accumulation of TAMs is associated with unfavorable clinical outcomes in numerous types of solid tumors. E-selectin is a hallmark of inflammation and a key adhesion molecule that accommodates the initial contact of circulating immune cells with the inflamed vessel surface. Currently, the association between E-selectin and TAMs is not fully elucidated; therefore, the present study investigated the association between vessel inflammation, TAM infiltration, and clinical outcome in breast cancer. A total of 53 procedure-naïve invasive breast cancer cases were immunohistochemically analyzed for the presence of cluster of differentiation (CD)68 TAMs, E-selectin vessels and tumor inflammation. The association between CD68 and E-selectin expression, and tumor inflammation as well as overall survival was evaluated using Kaplan-Meier survival curves and multivariable Cox's proportional hazards regression analysis. The abundance of TAMs was identified to be positively associated with tumor inflammation, estrogen receptor and E-selectin expression levels. A greater prevalence of TAMs and tumor inflammation was significantly associated with shorter overall survival times. E-selectin expression levels were significantly higher in tumor vessels among elderly patients, but were not associated with overall survival. The abundance of TAMs was associated with the presence of E-selectin-expressing inflamed tumor vessels and tumor inflammation, as well as overall survival in patients with invasive breast carcinoma.
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http://dx.doi.org/10.3892/ol.2017.6466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530034PMC
August 2017

Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment.

Cancer Cell 2017 02;31(2):194-207

Department of Biomedical Sciences, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Refractoriness of solid tumors, including colorectal cancers (CRCs), to immunotherapies is attributed to the immunosuppressive tumor microenvironment that protects malignant cells from cytotoxic T lymphocytes (CTLs). We found that downregulation of the type I interferon receptor chain IFNAR1 occurs in human CRC and mouse models of CRC. Downregulation of IFNAR1 in tumor stroma stimulated CRC development and growth, played a key role in formation of the immune-privileged niche, and predicted poor prognosis in human CRC patients. Genetic stabilization of IFNAR1 improved CTL survival and increased the efficacy of the chimeric antigen receptor T cell transfer and PD-1 inhibition. Likewise, pharmacologic stabilization of IFNAR1 suppressed tumor growth providing the rationale for upregulating IFNAR1 to improve anti-cancer therapies.
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http://dx.doi.org/10.1016/j.ccell.2017.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313042PMC
February 2017

E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases.

Mol Ther Nucleic Acids 2016 Dec 13;5(12):e399. Epub 2016 Dec 13.

University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.

E-selectin is an adhesion molecule expressed on the luminal surface of inflamed blood vessels that mediates hematogenous metastasis by assisting shear-resistant adhesion of circulating tumor cells to the vessel surface under dynamic blood flow. Previously, we developed an E-selectin antagonistic thioaptamer (ESTA) for the prevention of hematogenous metastasis through the blockade of CD44 breast cancer cells (BCa) adhesion to E-selectin-expressing premetastatic endothelial niche. The current study focuses on developing a PEGylated E-selectin targeting thioaptamer with improved pharmaceutical properties. A serial deletion of stem-loops reveled that loop-1 and -2 (ESTA7) are the minimally effective backbone structure necessary to obtain inhibition of the E-selectin/CD44 interaction and shear resistant adhesion of CD44 BCa to E-selectin-expressing human endothelial cells (HMVECs) at a level equal to ESTA. Chemical conjugation of methoxy-polyethylene-glycol (PEG) at the sizes of 5 and 10 kDa did not interfere with ESTA7-mediated shear-resistant adhesion. However, in vivo study demonstrated that only 10 kDa PEG-conjugated ESTA7 (ESTA7-p10) retains the activity to inhibit metastases at a level equal to parental ESTA. Additionally, a single intravenous injection of ESTA7-p10 inhibited the development of lung, brain, and bone metastases of MDA-MB-231, through the blockade of E-selectin. Moreover, PEGylation led to an extension of elimination half-life and increase of AUC, resulting in superior inhibition of metastasis development compared to parental ESTA with a longer interval between dosing in a spontaneous metastasis model. Lastly, repeated intravenous administration of ESTA7-p10 was tolerated in mice, highlighting the potential prophylactic application of ESTA7-p10 for metastasis prevention.
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http://dx.doi.org/10.1038/mtna.2016.103DOI Listing
December 2016

Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation.

J Invest Dermatol 2016 10 29;136(10):1990-2002. Epub 2016 Jun 29.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Phototherapy with UV light is a standard treatment for psoriasis, yet the mechanisms underlying the therapeutic effects are not well understood. Studies in human and mouse keratinocytes and in the skin tissues from human patients and mice showed that UV treatment triggers ubiquitination and downregulation of the type I IFN receptor chain IFNAR1, leading to suppression of IFN signaling and an ensuing decrease in the expression of inflammatory cytokines and chemokines. The severity of imiquimod-induced psoriasiform inflammation was greatly exacerbated in skin of mice deficient in IFNAR1 ubiquitination (Ifnar1(SA)). Furthermore, these mice did not benefit from UV phototherapy. Pharmacologic induction of IFNAR1 ubiquitination and degradation by an antiprotozoal agent halofuginone also relieved psoriasiform inflammation in wild-type but not in Ifnar1(SA) mice. These data identify downregulation of IFNAR1 by UV as a major mechanism of the UV therapeutic effects against the psoriatic inflammation and provide a proof of principle for future development of agents capable of inducing IFNAR1 ubiquitination and downregulation for the treatment of psoriasis.
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http://dx.doi.org/10.1016/j.jid.2016.06.608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035634PMC
October 2016

Erratum to: The effect of soluble E-selectin on tumor progression and metastasis.

BMC Cancer 2016 06 28;16(1):370. Epub 2016 Jun 28.

Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.

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http://dx.doi.org/10.1186/s12885-016-2391-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926296PMC
June 2016

Validation of tumor protein marker quantification by two independent automated immunofluorescence image analysis platforms.

Mod Pathol 2016 10 17;29(10):1143-54. Epub 2016 Jun 17.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.

Protein marker levels in formalin-fixed, paraffin-embedded tissue sections traditionally have been assayed by chromogenic immunohistochemistry and evaluated visually by pathologists. Pathologist scoring of chromogen staining intensity is subjective and generates low-resolution ordinal or nominal data rather than continuous data. Emerging digital pathology platforms now allow quantification of chromogen or fluorescence signals by computer-assisted image analysis, providing continuous immunohistochemistry values. Fluorescence immunohistochemistry offers greater dynamic signal range than chromogen immunohistochemistry, and combined with image analysis holds the promise of enhanced sensitivity and analytic resolution, and consequently more robust quantification. However, commercial fluorescence scanners and image analysis software differ in features and capabilities, and claims of objective quantitative immunohistochemistry are difficult to validate as pathologist scoring is subjective and there is no accepted gold standard. Here we provide the first side-by-side validation of two technologically distinct commercial fluorescence immunohistochemistry analysis platforms. We document highly consistent results by (1) concordance analysis of fluorescence immunohistochemistry values and (2) agreement in outcome predictions both for objective, data-driven cutpoint dichotomization with Kaplan-Meier analyses or employment of continuous marker values to compute receiver-operating curves. The two platforms examined rely on distinct fluorescence immunohistochemistry imaging hardware, microscopy vs line scanning, and functionally distinct image analysis software. Fluorescence immunohistochemistry values for nuclear-localized and tyrosine-phosphorylated Stat5a/b computed by each platform on a cohort of 323 breast cancer cases revealed high concordance after linear calibration, a finding confirmed on an independent 382 case cohort, with concordance correlation coefficients >0.98. Data-driven optimal cutpoints for outcome prediction by either platform were reciprocally applicable to the data derived by the alternate platform, identifying patients with low Nuc-pYStat5 at ~3.5-fold increased risk of disease progression. Our analyses identified two highly concordant fluorescence immunohistochemistry platforms that may serve as benchmarks for testing of other platforms, and low interoperator variability supports the implementation of objective tumor marker quantification in pathology laboratories.
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http://dx.doi.org/10.1038/modpathol.2016.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047958PMC
October 2016

The effect of soluble E-selectin on tumor progression and metastasis.

BMC Cancer 2016 05 24;16:331. Epub 2016 May 24.

Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.

Background: Distant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer. We have previously reported that E-selectin expression on the endothelial cell surface mediates shear-resistant adhesion and migration of circulating cancer cells via interaction with CD44. As a result of shedding, soluble E-selectin (sE-selectin) from the activated endothelium is present in the serum. In this study, we aimed to understand the role of sE-selectin in tumor progression and metastasis.

Methods: We investigated the effect of sE-selectin on shear-resistant adhesion and migration of metastatic breast cancer cells and leukocytes in vitro and in vivo.

Results: We found that sE-selectin promoted migration and shear-resistant adhesion of CD44(+) (/high) breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to non-activated human microvessel endothelial cells (ES-HMVECs), but not of CD44(-/low) breast cancer cell lines (MCF-7 and T-47D). This endothelial E-selectin independent, sE-selectin-mediated shear-resistant adhesion was also observed in a leukocyte cell line (HL-60) as well as human peripheral blood mononuclear cells (PBMCs). Additionally, the incubation of MDA-MB-231 cells with sE-selectin triggered FAK phosphorylation and shear-resistant adhesion of sE-selectin-treated cells resulted in increased endothelial permeabilization. However, CD44 knockdown in MDA-MB-231 and HL-60 cells resulted in a significant reduction of sE-selectin-mediated shear-resistant adhesion to non-activated HMVECs, suggesting the involvement of CD44/FAK. Moreover, functional blockade of ICAM-1 in non-activated HMVECs resulted in a marked reduction of sE-selectin-mediated shear-resistant adhesion. Finally, the pre-incubation of CD44(+) 4 T1 murine breast cancer cells with sE-selectin augmented infiltration into the lung in E-selectin K/O mice and infusion of human PBMCs pre-incubated with sE-selectin stimulated MDA-MB-231 xenografted breast tumor growth in NSG mice.

Conclusions: Our data suggest that circulating sE-selectin stimulates a broad range of circulating cells via CD44 and mediates pleiotropic effects that promote migration and shear-resistant adhesion in an endothelial E-selectin independent fashion, in turn accelerating tissue infiltration of leukocytes and cancer cells.
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http://dx.doi.org/10.1186/s12885-016-2366-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879723PMC
May 2016

Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression.

Cell Rep 2016 Apr 24;15(1):171-180. Epub 2016 Mar 24.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Oncogene activation induces DNA damage responses and cell senescence. We report a key role of type I interferons (IFNs) in oncogene-induced senescence. IFN signaling-deficient melanocytes expressing activated Braf do not exhibit senescence and develop aggressive melanomas. Restoration of IFN signaling in IFN-deficient melanoma cells induces senescence and suppresses melanoma progression. Additional data from human melanoma patients and mouse transplanted tumor models suggest the importance of non-cell-autonomous IFN signaling. Inactivation of the IFN pathway is mediated by the IFN receptor IFNAR1 downregulation that invariably occurs during melanoma development. Mice harboring an IFNAR1 mutant, which is partially resistant to downregulation, delay melanoma development, suppress metastatic disease, and better respond to BRAF or PD-1 inhibitors. These results suggest that IFN signaling is an important tumor-suppressive pathway that inhibits melanoma development and progression and argue for targeting IFNAR1 downregulation to prevent metastatic disease and improve the efficacy of molecularly target and immune-targeted melanoma therapies.
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http://dx.doi.org/10.1016/j.celrep.2016.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826807PMC
April 2016

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer.

Am J Pathol 2015 Sep;185(9):2505-22

Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania; Prostate Cancer Discovery and Development Program, Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/b-induced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stem-like properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells.
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http://dx.doi.org/10.1016/j.ajpath.2015.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597281PMC
September 2015

Positive Association of Fibroadenomatoid Change with HER2-Negative Invasive Breast Cancer: A Co-Occurrence Study.

PLoS One 2015 22;10(6):e0129500. Epub 2015 Jun 22.

Biomedical Informatics, Windber Research Institute, Windber, Pennsylvania, United States of America.

Background: Risk assessment of a benign breast disease/lesion (BBD) for invasive breast cancer (IBC) is typically done through a longitudinal study. For an infrequently-reported BBD, the shortage of occurrence data alone is a limiting factor to conducting such a study. Here we present an approach based on co-occurrence analysis, to help address this issue. We focus on fibroadenomatoid change (FAC), an under-studied BBD, as our preliminary analysis has suggested its previously unknown significant co-occurrence with IBC.

Methods: A cohort of 1667 female patients enrolled in the Clinical Breast Care Project was identified. A single experienced breast pathologist reviewed all pathology slides for each case and recorded all observed lesions, including FAC. Fibroadenoma (FA) was studied for comparison since FAC had been speculated to be an immature FA. FA and Fibrocystic Changes (FCC) were used for method validation since they have been comprehensively studied. Six common IBC and BBD risk/protective factors were also studied. Co-occurrence analyses were performed using logistic regression models.

Results: Common risk/protective factors were associated with FA, FCC, and IBC in ways consistent with the literature in general, and they were associated with FAC, FA, and FCC in distinct patterns. Age was associated with FAC in a bell-shape curve so that middle-aged women were more likely to have FAC. We report for the first time that FAC is positively associated with IBC with odds ratio (OR) depending on BMI (OR = 6.78, 95%CI = 3.43-13.42 at BMI<25 kg/m2; OR = 2.13, 95%CI = 1.20-3.80 at BMI>25 kg/m2). This association is only significant with HER2-negative IBC subtypes.

Conclusions: We conclude that FAC is a candidate risk factor for HER2-negative IBCs, and it is a distinct disease from FA. Co-occurrence analysis can be used for initial assessment of the risk for IBC from a BBD, which is vital to the study of infrequently-reported BBDs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129500PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476726PMC
March 2016

Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice.

Toxicol Appl Pharmacol 2015 Aug 3;287(1):86-92. Epub 2015 Jun 3.

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK 73104, United States. Electronic address:

The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100μg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500μg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels of plasma cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions.
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http://dx.doi.org/10.1016/j.taap.2015.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966538PMC
August 2015