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Cancer Research

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https://www.readbyqxmd.com/read/28209621/prominent-oncogenic-roles-of-evi1-in-breast-carcinoma
#1
Hui Wang, Thorsten Schaefer, Martina Konantz, Martin Braun, Zsuzsanna Varga, Anna M Paczulla, Selina Reich, Francis Jacob, Sven Perner, Holger Moch, Tanja Fehm, Lothar Kanz, Klaus Schulze-Osthoff, Claudia Lengerke
Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma (BC) where its contributions are unexplored. Analyzing a tissue microarray of 608 BC patient specimens, we documented EVI1 overexpression in both estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC. Here we report prognostic relevance of EVI1 overexpression in triple-negative BC (TNBC) but not in the HER2-positive BC subset. In human breast cancer cells, EVI1 silencing reduced proliferation, apoptosis resistance and tumorigenicity, effects rescued by estrogen supplementation in ER+ BC cells...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209620/the-histone-methyltransferase-dot1l-promotes-neuroblastoma-by-regulating-gene-transcription
#2
Matthew Wong, Andrew El Tee, Giorgio Milazzo, Jessica L Bell, Rebecca C Poulos, Bernard Atmadibrata, Yuting Sun, Duohui Jing, Nicholas Ho, Dora Ling, Pei Yan Liu, Xu Dong Zhang, Stefan Hüttelmaier, Jason W H Wong, Jenny Wang, Patsie Polly, Giovanni Perini, Christopher J Scarlett, Tao Liu
Myc oncoproteins exert tumorigenic effects by regulating expression of target oncogenes. Histone H3 lysine 79 (H3K79) methylation at Myc-responsive elements of target gene promoters is a strict prerequisite for Myc-induced transcriptional activation, and DOT1L is the only known histone methyltransferase that catalyses H3K79 methylation. Here we show that N-Myc upregulatsd DOT1L mRNA and protein expression by binding to the DOT1L gene promoter. shRNA-mediated depletion of DOT1L reduced mRNA and protein expression of N-Myc target genes ODC1 and E2F2...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209619/lapatinib-resistance-in-breast-cancer-cells-is-accompanied-by-phosphorylation-mediated-reprogramming-of-glycolysis
#3
Benjamin Ruprecht, Esther A Zaal, Jana Zecha, Wei Wu, Celia R Berkers, Bernhard Kuster, Simone Lemeer
HER2/ERBB2-overexpressing breast cancers targeted effectively by the small molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteomic, kinomic, and phosphoproteomic changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209618/the-stat3-mirna-92-wnt-signaling-pathway-regulates-spheroid-formation-and-malignant-progression-in-ovarian-cancer
#4
Min-Wei Chen, Shu-Ting Yang, Ming-Hsien Chien, Kuo-Tai Hua, Chin-Jui Wu, Sheng-Mou Hsiao, Hao Lin, Michael Hsiao, Jen-Liang Su, Lin-Hung Wei
Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209617/loss-of-ndrg2-expression-confers-oral-squamous-cell-carcinoma-with-enhanced-metastatic-potential
#5
Tomohiro Tamura, Tomonaga Ichikawa, Shingo Nakahata, Yudai Kondo, Yuri Tagawa, Kouji Yamamoto, Kentaro Nagai, Takashi Baba, Ryoji Yamaguchi, Mitsuru Futakuchi, Yoshihiro Yamashita, Kazuhiro Morishita
Loss of the tumor suppressor NDRG2 has been implicated in the development of oral squamous cell carcinoma (OSCC), acting by modulating PI3K/AKT-mediated dephosphorylation of PTEN at S380/S382/T383 (STT). Here we show that the majority of OSCC tumors with lymph node metastasis, a major prognostic factor, exhibit high levels of phosphorylated AKT-S473 and PTEN-STT and low levels of NDRG2 expression. In Ndrg2-deficient mice, which develop a wide range of tumors, we developed a model of OSCC by treatment with the tobacco surrogate 4-nitroquinoline-1-oxide (4-NQO)...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209616/octn1-is-a-high-affinity-carrier-of-nucleoside-analogs
#6
Christina Drenberg, Alice A Gibson, Stanley Pounds, Lei Shi, Dena Rhinehart, Lie Li, Shuiying Hu, Guoqing Du, Anne T Nies, Matthias Schwab, Navjotsingh Pabla, William Blum, Tanja A Gruber, Sharyn D Baker, Alex Sparreboom
Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analog cytarabine...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209615/targeted-degradation-of-bet-proteins-in-triple-negative-breast-cancer
#7
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer L Meagher, Jeanne Stuckey, Daniel F Hayes, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209614/distinct-interactions-of-ebp1-isoforms-with-fbxw7-elicits-different-functions-in-cancer
#8
Yuli Wang, Pengju Zhang, Yunshan Wang, Panpan Zhan, Chunyan Liu, Jian-Hua Mao, Guangwei Wei
The ErbB3 receptor binding protein EBP1 encodes two alternatively spliced isoforms p48 and p42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. Here we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 p48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 p48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209613/wnt-%C3%AE-catenin-directs-self-renewal-symmetric-cell-division-of-hterthigh-prostate-cancer-stem-cells
#9
Kai Zhang, Yanjing Guo, Xue Wang, Huifang Zhao, Zhongzhong Ji, Chaping Cheng, Li Li, Yuxiang Fang, Dawei Xu, Helen He Zhu, Wei-Qiang Gao
Cancer stem-like cells (CSC) drive cancer progression and recurrence. Self-renewal expansion of CSC is achieved through symmetric cell division, yet how external stimuli affect intracellular regulatory programs of CSC division modes and stemness remains obscure. Here we report that hTERThigh prostate cancer (PCa) cells exhibit CSC properties, including a stem cell-associated gene expression signature, long term tumor-propagating capacity and epithelial-to-mensenchymal transition (EMT). In promoting the self-renewal symmetric division of hTERThigh PCa cells, WNT3a dramatically decreased the ratio of hTERThigh PCa cells undergoing asymmetric division...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209612/microrna-520f-reverses-epithelial-to-mesenchymal-transition-by-targeting-adam9-and-tgfbr2
#10
Jasmijn Gm van Kampen, Onno van Hooij, Cornelius Fj Jansen, Frank P Smit, Paula I van Noort, Iman J Schultz, Roel Qj Schaapveld, Jack A Schalken, Gerald W Verhaegh
Reversing epithelial-to-mesenchymal transition (EMT) in cancer cells has been widely considered as an approach to combat cancer progression and therapeutic resistance, but a limited number of broadly comprehensive investigations of microRNAs involved in this process have been conducted. In this study, we screened a library of 1120 microRNA for their ability to transcriptionally activate the E-cadherin gene CDH1 in a promoter reporter assay as a measure of EMT reversal. By this approach, we defined miR-520f as a novel EMT-reversing microRNA...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209611/genetic-manipulation-of-helicobacter-pylori-virulence-function-by-host-carcinogenic-phenotypes
#11
Giovanni Suarez, Judith Romero-Gallo, Johanna C Sierra, M Blanca Piazuelo, Uma Krishna, Martin Alonso Gomez, Keith T Wilson, Richard M Peek
Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the cag type 4 secretion system (cagT4SS), which translocates an oncoprotein into host cells. A structural component of the cagT4SS is CagY, which become rapidly altered during in vivo adaptation in mice and rhesus monkeys, rendering the cagT4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the H...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209610/the-tumor-microenvironment-at-a-turning-point-knowledge-gained-over-the-last-decade-and-challenges-and-opportunities-ahead-a-white-paper-from-the-nci-tme-network
#12
Yves A DeClerck, Kenneth J Pienta, Elisa C Woodhouse, Dinah S Singer, Suresh Mohla
Over the past 10 years, the Tumor Microenvironment Network (TMEN), supported by the NCI (Bethesda, MD), has promoted collaborative research with the explicit goal of fostering multi-institutional and transdisciplinary groups that are capable of addressing complex issues involving the tumor microenvironment. The main goal of the TMEN was to generate novel information about the dynamic complexity of tumor-host interactions in different organ systems with emphasis on using human tissues and supplemented by experimental models...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28209609/pancreatic-cancer-progress-and-challenges-in-a-rapidly-moving-field
#13
Eric A Collisson, Kenneth P Olive
"Pancreatic Cancer: Advances in Science and Clinical Care," a Special Conference of the American Association for Cancer Research, was held in Orlando, FL, on May 12 to 15, bringing together more than 450 basic, translational, clinical, and epidemiologic pancreatic cancer researchers as well as pancreatic cancer patients, survivors, and advocates. Pancreatic cancer remains one of the great challenges in medicine, but the accelerating pace of research and early hints of clinical successes to come were palpable throughout the meeting...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202532/cd40-signaling-drives-potent-cellular-immune-responses-in-heterologous-cancer-vaccinations
#14
Supot Nimanong, Dmitrij Ostroumov, Jessica Wingerath, Sarah Knocke, Norman Woller, Engin Guerlevik, Christine Falk, Michael P Manns, Florian Kuehnel, Thomas C Wirth
Antagonistic antibodies targeting co-inhibitory receptors have revolutionized the treatment of cancer by inducing durable immune responses and clinical remissions in patients. In contrast, success of agonistic costimulatory antibodies has thus far been limited due to insufficient induction of adaptive immune responses. Here we describe a novel vaccination method consisting of a primary dendritic cell immunization followed by a composite vaccination including an agonistic CD40 antibody, soluble antigen and a TLR3 agonist, referred to as CoAT...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202531/the-role-of-megakaryocytes-in-breast-cancer-metastasis-to-bone
#15
Walter Jackson, Donna M Sosnoski, Sara E Ohanessian, Paige Chandler, Adam W Mobley, Kacey D Meisel, Andrea M Mastro
Little is known about how megakaryocytes affect metastasis apart from serving as the source of platelets. We noted an increase in the number of megakaryocytes in the femurs of metastases-bearing athymic mice four weeks following intracardiac inoculation of MDA-MB-231 human breast cancer cells. How did the megakaryocytes relate to the metastases? Did megakaryocytes prepare a niche or did they increase in response to metastases? To test these possibilities, we examined two models of experimental metastasis, intracardiac inoculation of human MDA-MB-231 into athymic mice, and intramammary injection of mouse tumor cells, 4T1...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202530/therapeutic-potential-of-bacteria-against-solid-tumors
#16
Haralampos Hatzikirou, Juan Carlos Lopez Alfonso, Sara Leschner, Siegfried Weiss, Michael Meyer-Hermann
Intentional bacterial infections can produce efficacious anti-tumor responses in mice, rats, dogs and humans. However, low overall success rates and intense side-effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the pro-inflammatory cytokine TNF-α in a set of established murine models of cancer. To interpret the experiments conducted, we considered and calibrated a tumor-effector cell recruitment model under the influence of functional tumor-associated vasculature...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202529/aberrant-syk-kinase-signaling-is-essential-for-tumorigenesis-induced-by-tsc2-inactivation
#17
Ye Cui, Wendy K Steagall, Anthony Lamattina, Gustavo Pacheco-Rodriguez, Mario Stylianou, Pranav Kidambi, Benjamin Stump, Fernanda Golzarri, Ivan O Rosas, Carmen Priolo, Elizabeth P Henske, Joel Moss, Souheil El-Chemaly
Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis (LAM), a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogeneic growth factor VEGF-D are elevated significantly in LAM. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in LAM. Here we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from LAM patients contributes to tumor growth...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202528/distinct-levels-of-radioresistance-in-lgr5-colonic-epithelial-stem-cells-versus-lgr5-small-intestinal-stem-cells
#18
Guoqiang Hua, Chu Wang, Yan Pan, Zhaoshi Zeng, Sang Gyu Lee, Maria Laura Martin, Adriana Haimovitz-Friedman, Zvi Fuks, Philip B Paty, Richard N Kolesnick
While small and large intestines possess seemingly similar Wnt-driven Leucine-rich repeat-containing G protein coupled receptor 5 (Lgr5)+ adult epithelial stem cells, we report here that the two organs exhibit distinct mechanisms of tissue response to ionizing radiation. Employing Lgr5-lacZ transgenic mice and Lgr5 in situ hybridization, we found colonic epithelial stem cells (CESC) markedly more radioresistant in vivo than small intestinal crypt base columnar stem cells (CBC) (D0 6.0±0.3 Gy vs. 1.3±0.1, respectively; p0...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202527/-18f-2s-4r-4-fluoroglutamine-pet-detects-glutamine-pool-size-changes-in-triple-negative-breast-cancer-in-response-to-glutaminase-inhibition
#19
Rong Zhou, Austin R Pantel, Shihong Li, Brian P Lieberman, Karl Ploessl, Hoon Choi, Eric Blankemeyer, Hsiaoju Lee, Hank Kung, Robert H Mach, David Mankoff
Glutaminolysis is a metabolic pathway adapted by many aggressive cancers, including triple-negative breast cancers (TNBC), to utilize glutamine for survival and growth. In this study, we examined the utility of [18F](2S,4R)4-fluoroglutamine ([18F]4F-Gln) PET to measure tumor cellular glutamine pool size, whose change might reveal the pharmacodynamic (PD) effect of drugs targeting this cancer-specific metabolic pathway. High glutaminase (GLS) activity in TNBC tumors resulted in low cellular glutamine pool size assayed via high-resolution 1H magnetic resonance spectroscopy (MRS)...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202526/radiation-resistance-in-kras-mutated-lung-cancer-is-enabled-by-stem-like-properties-mediated-by-an-osteopontin-egfr-pathway
#20
Meng Wang, Jing Han, Lynnette Marcar, Josh Black, Qi Liu, Xiangyong Li, Kshithija Nagulapalli, Lecia V Sequist, Raymond H Mak, Cyril H Benes, Theodore S Hong, Kristin Gurtner, Mechthild Krause, Michael Baumann, Jing X Kang, Johnathan Whetstine, Henning Willers
Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype...
February 15, 2017: Cancer Research
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