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Molecular Cancer Research: MCR

Min Yao, Wei Fang, Curtis Smart, Qingting Hu, Shixia Huang, Nehemiah Alvarez, Patrick Fields, Nikki Cheng
Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor and Her2 expression, and are resistant to anti-hormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage dependent mechanisms...
November 16, 2018: Molecular Cancer Research: MCR
Kathryn T Baker, Daniela Nachmanson, Shilpa Kumar, Mary J Emond, Cigdem Ussakli, Teresa A Brentnall, Scott R Kennedy, Rosa Ana Risques
The role of mitochondrial DNA (mtDNA) mutations in cancer remains controversial. Ulcerative Colitis (UC) is an inflammatory bowel disease that increases the risk of colorectal cancer and involves mitochondrial dysfunction, making it an ideal model to study the role of mtDNA in tumorigenesis. Our goal was to comprehensively characterize mtDNA mutations in UC tumorigenesis using Duplex Sequencing, an ultra-accurate next generation sequencing method. We analyzed 46 colon biopsies from non-UC and UC patients with and without cancer, including biopsies at all stages of dysplastic progression...
November 16, 2018: Molecular Cancer Research: MCR
Wei Xiao, Mohammed L Ibrahim, Priscilla S Redd, John D Klement, Chunwan Lu, Dafeng Yang, Natasha M Savage, Kebin Liu
Despite the remarkable efficacy of immune checkpoint inhibitor (ICI) immunotherapy in various types of human cancers, colon cancer, except for the approximately 4% microsatellite-instable (MSI) colon cancer, does not respond to ICI immunotherapy. ICI acts through activating cytotoxic T lymphocytes (CTLs) that use the Fas-FasL pathway as one of the two effector mechanisms to suppress tumor. Cancer stem cells are often associated with resistance to therapy including immunotherapy, but the functions of Fas in colon cancer apoptosis and colon cancer stem cells are currently conflicting and highly debated...
November 14, 2018: Molecular Cancer Research: MCR
Todd A Hopkins, William B Ainsworth, Paul A Ellis, Cherrie K Donawho, Enrico L DiGiammarino, Sanjay C Panchal, Vivek C Abraham, Mikkel A Algire, Yan Shi, Amanda M Olson, Eric F Johnson, Julie L Wilsbacher, David Maag
Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic BRCA-associated breast cancer, and ongoing studies are exploring additional indications and combinations with other agents. PARP inhibitors trap PARP onto damaged chromatin when combined with temozolomide and methyl methanesulfonate, but the clinical relevance of these findings remains unknown. PARP trapping has thus far been undetectable in cancer cells treated with PARP inhibitors alone...
November 14, 2018: Molecular Cancer Research: MCR
Xiaorong Zhou, Mahesh S Padanad, Bret M Evers, Bethany Smith, Nicole Novaresi, Shruthy Suresh, James A Richardson, Emily Stein, JIngfei Zhu, Robert E Hammer, Kathryn A O'Donnell
PROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. While PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest context-dependent functions for PCDH7 in distinct tumor types. Given that PCDH7 is a potentially targetable molecule on the surface of cancer cells, further investigation of its role in tumorigenesis in vivo is needed to evaluate the therapeutic potential of its inhibition...
November 8, 2018: Molecular Cancer Research: MCR
Yongxu Zhao, Tao Yu, Nan Zhang, Jianxia Chen, Peng Zhang, Shuang Li, Lijun Luo, Zhenling Cui, Yue Qin, Feng Liu
The E-cadherin/β-catenin signaling pathway plays a critical role in the maintenance of epithelial architecture and regulation of tumor progression. Normally, E-cadherin locates on the cell surface with its cytosolic domain linking to the actin cytoskeleton through interaction with catenins. Although the nuclear localization of E-cadherin has been frequently observed in various types of cancers, little is known regarding the functional consequences of its nuclear translocation. Here, we showed that in colorectal cancer samples and cell lines, E-cadherin localized in the nucleus; and the nuclear localization was mediated through protein interaction with CTNND1...
November 6, 2018: Molecular Cancer Research: MCR
Simon Garinet, Geraldine Pignot, Sophie Vacher, Constance Le Goux, Anne Schnitzler, Walid Chemlali, Sirab Nanor, Nicolas Barry Delongchamps, Marc Zerbib, Mathilde Sibony, Yves Allory, Diane Damotte, Ivan Bieche
Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, non-coding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 non-muscle invasive bladder cancers (NMIBC) and 59 muscle invasive bladder cancers (MIBC)...
November 6, 2018: Molecular Cancer Research: MCR
Chiara Bellio, Celeste DiGloria, Rosemary Foster, Kaitlyn James, Panagiotis A Konstantinopoulos, Whitfield B Growdon, Bo R Rueda
Poly (ADP-ribose) polymerase inhibitors (PARPi) are FDA approved monotherapy agents for the treatment of recurrent ovarian cancer (OvCa) in patients with and without a BRCA mutation. Despite promising response rates, not all patients derive benefit and the majority develop resistance. PARPi treatment in vitro and in vivo induced an enrichment of CD133+ and CD117+ ovarian cancer stem cells (CSCs). This effect was not impacted by BRCA mutation status. In the CSC fractions, PARPi induced cell cycle arrest in G2/M with a consequent accumulation of yH2AX, RAD51 and uniquely DMC1 foci...
November 6, 2018: Molecular Cancer Research: MCR
Fengju Chen, Yiqun Zhang, Sooryanarayana Varambally, Chad J Creighton
Tumor metastasis is a major contributor to cancer patient mortality, but the process remains poorly understood. Molecular comparisons between primary tumors and metastases can provide insights into the pathways and processes involved. Here, we systematically analyzed and cataloged molecular correlates of metastasis using The Cancer Genome Atlas (TCGA) datasets across 11 different cancer types, these data involving 4,473 primary tumor samples and 395 tumor metastasis samples (including 369 from melanoma). For each cancer type, widespread differences in gene transcription between primary and metastasis samples were observed...
November 6, 2018: Molecular Cancer Research: MCR
Kristen S Hill, Evan R Roberts, Xue Wang, Ellen Marin, Taeeun D Park, Sorany Son, Yuan Ren, Bin Fang, Sean Yoder, Sungjune Kim, Lixin Wan, Amod A Sarnaik, John M Koomen, Jane L Messina, Jamie K Teer, Youngchul Kim, Jie Wu, Charles E Chalfant, Minjung Kim
Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells...
October 24, 2018: Molecular Cancer Research: MCR
Eric P Rahrmann, Natalie K Wolf, George M Otto, Lynn Heltemes Harris, Laura B Ramsey, Jingmin Shu, Rebecca S LaRue, Michael A Linden, Susan K Rathe, Timothy K Starr, Michael A Farrar, Branden S Moriarity, David A Largaespada
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements and gene expression patterns. Here it is demonstrated that early B cell progenitors express 2',3'-Cyclic-nucleotide 3' phosphodiesterase (CNP) and that when targeted with Sleeping Beauty (SB) mutagenesis, Trp53R270H mutation or Pten loss gave rise to highly-penetrant lymphoid diseases, predominantly FL and DLBCL. In efforts to identify genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of SB-mutagenized mice (n=23) and SB-mutagenized mice on a Trp53R270H background (n=7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively...
October 24, 2018: Molecular Cancer Research: MCR
Ahmed Basudan, Nolan Priedigkeit, Ryan J Hartmaier, Ethan S Sokol, Amir Bahreini, Rebecca J Watters, Michelle M Boisen, Rohit Bhargava, Kurt R Weiss, Maria M Karsten, Carsten Denkert, Jens-Uwe Blohmer, Jose P Leone, Ronald L Hamilton, Adam M Brufsky, Esther Elishaev, Peter C Lucas, Adrian V Lee, Steffi Oesterreich
DNA sequencing has identified a limited number of driver mutations in metastatic breast cancer beyond single base-pair mutations in the estrogen receptor (ESR1). However, our previous studies and others have observed that structural variants, such as ESR1 fusions, may also play a role. Therefore, we expanded upon these observations by performing a comprehensive and highly sensitive characterization of copy number (CN) alterations in a large clinical cohort of metastatic specimens. NanoString DNA hybridization was utilized to measure CN gains, amplifications and deletions of 67 genes in 108 breast cancer metastases, and in 26 cases, the patient-matched primary tumor...
October 24, 2018: Molecular Cancer Research: MCR
Yuqing Zhang, Amanda Kirane, Huocong Huang, Noah B Sorrelle, Francis J Burrows, Michael T Dellinger, Rolf A Brekken
Resistance to standard therapy remains a major challenge in the treatment of pancreatic ductal adenocarcinoma (PDA). Although anti-VEGF therapy delays PDA progression, therapy-induced hypoxia results in a less differentiated mesenchymal-like tumor cell phenotype, which reinforces the need for effective companion therapies. COX-2 inhibition has been shown to promote tumor cell differentiation and improve standard therapy response in PDA. Here, we evaluate the efficacy of COX-2 inhibition and VEGF blockade in preclinical models of PDA...
October 17, 2018: Molecular Cancer Research: MCR
Habiba Elfandy, Joshua Armenia, Filippo Pederzoli, Eli Pullman, Nelma Pértega-Gomes, Nikolaus Schultz, Kartik Viswanathan, Aram Vosoughi, Mirjam Blattner, Konrad H Stopsack, Giorgia Zadra, Kathryn L Penney, Juan Miguel Mosquera, Svitlana Tyekucheva, Lorelei A Mucci, Christopher Barbieri, Massimo Loda
Among prostate cancers (PCa) containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinico-pathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared to non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (n=164) had distinctive molecular features when compared to NC4 (n=102). These include: 1) Increased somatic copy number variations, specifically deletions at 6q, 8p which encompassed PTEN and MAP3K7 losses and gains at 3q; 2) Increased SPOPmut and ATMmut; 3) Enrichment for mTORC1 and MYC pathways by gene expression; 4) Increased methylation of selected genes...
October 17, 2018: Molecular Cancer Research: MCR
Ashley Mooneyham, Yoshie Iizuka, Qing Yang, Courtney Coombes, Mark McClellan, Vijayalakshmi Shridhar, Edith Emmings, Mihir Shetty, Liqiang Chen, Teng Ai, Joyce Meints, Michael K Lee, Melissa Gardner, Martina Bazzaro
UNC-45A, a highly conserved member of the UCS (UNC45A/CRO1/SHE4P) protein family of cochaperones, plays an important role in regulating cytoskeletal-associated functions in invertebrates and mammalian cells, including cytokinesis, exocytosis, cell motility, and neuronal development. Here, for the first time, UNC-45A is demonstrated to function as a mitotic spindle-associated protein that destabilizes microtubules (MT) activity. Using in vitro biophysical reconstitution and total internal reflection fluorescence microscopy analysis, we reveal that UNC-45A directly binds to taxol-stabilized MTs in the absence of any additional cellular cofactors or other MT-associated proteins and acts as an ATP-independent MT destabilizer...
October 15, 2018: Molecular Cancer Research: MCR
Chieh-Hsiang Chan, Chun-Ming Chen, Yan-Hwa Wu Lee, Li-Ru You
The pleiotropic roles of DEAD-box helicase 3, X-linked (DDX3X), including its functions in transcriptional and translational regulation, chromosome segregation, DNA damage, and cell growth control, have highlighted the association between DDX3X and tumorigenesis. However, mRNA transcripts and protein levels of DDX3X in patient specimens have shown the controversial correlations of DDX3X with hepatocellular carcinoma (HCC) prevalence. In this study, generation of hepatocyte-specific Ddx3x -knockout mice revealed that loss of Ddx3x facilitates liver tumorigenesis...
October 8, 2018: Molecular Cancer Research: MCR
Haley D Axelrod, Kenneth C Valkenburg, Sarah R Amend, Jessica L Hicks, Princy Parsana, Gonzalo Torga, Angelo M DeMarzo, Kenneth J Pienta
Prostate cancer bone metastasis remains lethal and incurable, and often arises years after elimination of the primary tumor. It is unclear what underlies the decades-long clinical latency before recurrence, but evidence points to the existence of dormant residual tumor cells that disseminated before the primary tumor was eliminated. To design therapies to prevent progression of disseminated tumor cells (DTC) into lethal metastases, it is crucial to understand the mechanism(s) underlying this dormancy. The current study functionally validated our previous observation that implicated the GAS6/AXL axis in mediating DTC dormancy in the bone marrow...
October 5, 2018: Molecular Cancer Research: MCR
Ida Aronchik, Yumin Dai, Matt Labenski, Carmen Barnes, Terri Jones, Lixin QIao, Lisa Beebe, Mehnaz Malek, Winfried Elis, Tao Shi, Konstantinos Mavrommatis, Gordon L Bray, Ellen H Filvaroff
As a critical signaling node, extracellular signal-regulated kinases (ERK1/2) are attractive drug targets, particularly in tumors driven by activation of the Mitogen Activated Protein Kinase (MAPK) pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant-BRAF activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF...
October 1, 2018: Molecular Cancer Research: MCR
Ho Yeon Lee, Junghwa Cha, Seon Kyu Kim, Jun Hyung Park, Ki Hoon Song, Pilnam Kim, Mi-Young Kim
Brain metastasis in breast cancer is particularly deadly, but effective treatments remain out of reach due to insufficient information about the mechanisms underlying brain metastasis and the potential vulnerabilities of brain-metastatic breast cancer cells. Here, human breast cancer cells and their brain-metastatic derivatives (BrMs) were used to investigate synthetic lethal interactions in BrMs. First, it was demonstrated that c-MYC activity is increased in BrMs and is required for their brain-metastatic ability in a mouse xenograft model...
September 28, 2018: Molecular Cancer Research: MCR
Mahsa Zarei, Shruti Lal, Ali Vaziri-Gohar, Kevin O'Hayer, Venugopal Gunda, Pankaj K Singh, Jonathan R Brody, Jordan M Winter
Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of α-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT...
September 28, 2018: Molecular Cancer Research: MCR
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