Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx
This study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the steroid hormone transporter OATP1B3 (SLCO1B3). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (Km = 23.2 μmol/L; Vmax = 321.6 pmol/mg/minute), and cells expressing a doxycycline-inducible SLCO1B3 construct had greater uptake of a clinically relevant concentration of 3H-testosterone (50 nmol/L; 1.6-fold, P = 0.0027). When compared with Slco1b2 (–/–) mice, Slco1b2 (–/–)/hSLCO1B3 knockins had greater ...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Sissung, T. M., Ley, A. M., Strope, J. D., McCrea, E. M., Beedie, S., Peer, C. J., Shukla, S., van Velkinburgh, J., Reece, K., Troutman, S., Campbell, T., Fernandez, E., Huang, P., Smith, J., Thakkar, N., Venzon, D. J., Brenner, S., Lee, W., Merino, M., L Tags: Signal Transduction Source Type: research

EGFR Signals through a DOCK180-MLK3 Axis to Drive Glioblastoma Cell Invasion
In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR–DOCK180–RAC1–MLK3–JNK signaling axis that drives gliobl...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Misek, S. A., Chen, J., Schroeder, L., Rattanasinchai, C., Sample, A., Sarkaria, J. N., Gallo, K. A. Tags: Signal Transduction Source Type: research

Regulation of USP37 Expression by REST-Associated G9a-Dependent Histone Methylation
The deubiquitylase (DUB) USP37 is a component of the ubiquitin system and controls cell proliferation by regulating the stability of the cyclin-dependent kinase inhibitor 1B, (CDKN1B/p27Kip1). The expression of USP37 is downregulated in human medulloblastoma tumor specimens. In the current study, we show that USP37 prevents medulloblastoma growth in mouse orthotopic models, suggesting that it has tumor-suppressive properties in this neural cancer. Here, we also report on the mechanism underlying USP37 loss in medulloblastoma. Previously, we observed that the expression of USP37 is transcriptionally repressed by the RE1 sil...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Dobson, T. H. W., Hatcher, R. J., Swaminathan, J., Das, C. M., Shaik, S., Tao, R.-H., Milite, C., Castellano, S., Taylor, P. H., Sbardella, G., Gopalakrishnan, V. Tags: Oncogenes and Tumor Suppressors Source Type: research

Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP
Reducing the levels of the androgen receptor (AR) is one of the most viable approaches to combat castration-resistant prostate cancer. Previously, we observed that proteasomal-dependent degradation of AR in response to 2-methoxyestradiol (2-ME) depends primarily on the E3 ligase C-terminus of HSP70-interacting protein (STUB1/CHIP). Here, 2-ME stimulation activates CHIP by phosphorylation via Aurora kinase A (AURKA). Aurora A kinase inhibitors and RNAi knockdown of Aurora A transcript selectively blocked CHIP phosphorylation and AR degradation. Aurora A kinase is activated by 2-ME in the S-phase as well as during mitosis, a...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Sarkar, S., Brautigan, D. L., Larner, J. M. Tags: Oncogenes and Tumor Suppressors Source Type: research

p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes
In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression. Mol Cancer Res; 15(8); 1051–62. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Pappas, K., Xu, J., Zairis, S., Resnick-Silverman, L., Abate, F., Steinbach, N., Ozturk, S., Saal, L. H., Su, T., Cheung, P., Schmidt, H., Aaronson, S., Hibshoosh, H., Manfredi, J., Rabadan, R., Parsons, R. Tags: Oncogenes and Tumor Suppressors Source Type: research

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer
This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040–50. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Sokolowska-Wedzina, A., Chodaczek, G., Chudzian, J., Borek, A., Zakrzewska, M., Otlewski, J. Tags: Oncogenes and Tumor Suppressors Source Type: research

miR-202 Diminishes TGF{beta} Receptors and Attenuates TGF{beta}1-Induced EMT in Pancreatic Cancer
Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs to regulate endogenous TGFβ1 levels via miR-663/4787-mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). Although DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFβ receptors, TGFBR1 and TGFBR...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Mody, H. R., Hung, S. W., Pathak, R. K., Griffin, J., Cruz-Monserrate, Z., Govindarajan, R. Tags: Oncogenes and Tumor Suppressors Source Type: research

Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer
Despite the known importance of androgen receptor (AR) signaling in prostate cancer, the processes downstream of AR that drive disease development and progression remain poorly understood. This knowledge gap has thus limited the ability to treat cancer. Here, it is demonstrated that androgens increase the metabolism of glutamine in prostate cancer cells. This metabolism was required for maximal cell growth under conditions of serum starvation. Mechanistically, AR signaling promoted glutamine metabolism by increasing the expression of the glutamine transporters SLC1A4 and SLC1A5, genes commonly overexpressed in prostate can...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: White, M. A., Lin, C., Rajapakshe, K., Dong, J., Shi, Y., Tsouko, E., Mukhopadhyay, R., Jasso, D., Dawood, W., Coarfa, C., Frigo, D. E. Tags: Metabolism Source Type: research

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models
This study describes a sensitive method to identify contaminating host reads in xenograft and explant DNA- and RNA-Seq data and is applicable to other forms of deep sequencing. Mol Cancer Res; 15(8); 1012–6. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Khandelwal, G., Girotti, M. R., Smowton, C., Taylor, S., Wirth, C., Dynowski, M., Frese, K. K., Brady, G., Dive, C., Marais, R., Miller, C. Tags: Genomics Source Type: research

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression
This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass. Mol Cancer Res; 15(8); 998–1011. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Fedele, V., Dai, F., Masilamani, A. P., Heiland, D. H., Kling, E., Gätjens-Sanchez, A. M., Ferrarese, R., Platania, L., Soroush, D., Kim, H., Nelander, S., Weyerbrock, A., Prinz, M., Califano, A., Iavarone, A., Bredel, M., Carro, M. S. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe
The current integrative pathobiologic hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation–based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in three-dimensional spheroids and organoids. The combination also reduces the growth of PDAC xenog...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Mathison, A., Salmonson, A., Missfeldt, M., Bintz, J., Williams, M., Kossak, S., Nair, A., de Assuncao, T. M., Christensen, T., Buttar, N., Iovanna, J., Huebert, R., Lomberk, G. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors
Novel discoveries involving the evaluation of potential therapeutics are based on newly identified molecular targets for atypical teratoid rhabdoid tumors (ATRT), which are the most common form of infantile brain tumors. Central nervous system ATRTs are rare, aggressive, and fast growing tumors of the brain and spinal cord and carry a very poor prognosis. Currently, the standard of care for ATRT patients is based on surgical resection followed by systemic chemotherapy and radiotherapy, which result in severe side effects. As protein tyrosine kinases have proven to be actionable targets that reduce tumor growth in a number ...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Messerli, S. M., Hoffman, M. M., Gnimpieba, E. Z., Bhardwaj, R. D. Tags: Cell Death and Survival Source Type: research

IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors
In conclusion, IGH/MYC–positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies. Implications: This study postulates that IGH/MYC–induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpg. Mol Cancer Res; 15(8); 967–72. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Maifrede, S., Martin, K., Podszywalow-Bartnicka, P., Sullivan-Reed, K., Langer, S. K., Nejati, R., Dasgupta, Y., Hulse, M., Gritsyuk, D., Nieborowska-Skorska, M., Lupey-Green, L. N., Zhao, H., Piwocka, K., Wasik, M. A., Tempera, I., Skorski, T. Tags: Rapid Impact Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Novel Insights into Gastric Cancer: Methylation of R-spondins and Regulation of LGR5 by SP1
This report identifies a regulatory mechanism of LGR5 expression in gastric carcinogenesis, with SP1 as an important component of the transcriptional complex and LGR5 activity, which is modulated by its ligands RSPO1 and RSPO2, whose expression is modulated by methylation. Visual Overview: http://mcr.aacrjournals.org/content/15/6/776/F1.large.jpg. Mol Cancer Res; 15(6); 776–85. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Wilhelm, F., Simon, E., Böger, C., Behrens, H.-M., Krüger, S., Röcken, C. Tags: Signal Transduction Source Type: research

INPP4B and PTEN Loss Leads to PI-3,4-P2 Accumulation and Inhibition of PI3K in TNBC
Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients, and still lacks an effective targeted therapy. Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer. Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4'-phosphate of phosphatidylinositol-(3, 4)-bisphosphate (PI-3,4-P2), creating phosphatidylinositol-3-phosphate. There is debate concer...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Reed, D. E., Shokat, K. M. Tags: Signal Transduction Source Type: research

Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression
This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on cancer cells. Mol Cancer Res; 15(6); 753–64. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Kasikara, C., Kumar, S., Kimani, S., Tsou, W.-I., Geng, K., Davra, V., Sriram, G., Devoe, C., Nguyen, K.-Q. N., Antes, A., Krantz, A., Rymarczyk, G., Wilczynski, A., Empig, C., Freimark, B., Gray, M., Schlunegger, K., Hutchins, J., Kotenko, S. V., Birge, Tags: Signal Transduction Source Type: research

Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1
In conclusion, robust and ubiquitous expression of DCLK1 was first demonstrated here in human PNET tissue specimens and cells. DCLK1 characterized the PNET cell behavior, inducing p-FAK/SLUG-mediated EMT. These findings suggest the possibility of developing novel therapeutic strategies against PNETs by targeting DCLK1. Implications: Evidence here reveals that human PNETs diffusely and robustly express the cancer stem cell marker DCLK1, which drives SLUG-mediated EMT, and suggests that NETs share biological features for druggable targets with other tumors, including neuroblastoma that also highly expresses DCLK1. Mol Cancer...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ikezono, Y., Koga, H., Akiba, J., Abe, M., Yoshida, T., Wada, F., Nakamura, T., Iwamoto, H., Masuda, A., Sakaue, T., Yano, H., Tsuruta, O., Torimura, T. Tags: Signal Transduction Source Type: research

The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53
The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to IFN. Recently, a few A3 genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes, we show that under stress conditions and immune challenges, all A3 genes are direct transcriptional targets of the tumor suppressor p53. Although the expression of most A3 genes (including A3C and A3H) was stimulated by the activation of p53, treatment with the DNA-damaging agent doxorubicin or the p53 sta...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Menendez, D., Nguyen, T.-A., Snipe, J., Resnick, M. A. Tags: Oncogenes and Tumor Suppressors Source Type: research

Hypoxia Selectively Enhances Integrin {alpha}5{beta}1 Receptor Expression in Breast Cancer to Promote Metastasis
Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate th...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ju, J. A., Godet, I., Ye, I. C., Byun, J., Jayatilaka, H., Lee, S. J., Xiang, L., Samanta, D., Lee, M. H., Wu, P.-H., Wirtz, D., Semenza, G. L., Gilkes, D. M. Tags: Oncogenes and Tumor Suppressors Source Type: research

Atorvastatin Decreases HBx-Induced Phospho-Akt in Hepatocytes via P2X Receptors
Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer-related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol-lowering drugs, and recent epidemiologic evidence suggests that statins prevent aggressive HCC development. Previous experiments revealed that statins downregulate phosphorylated Akt (pAkt). Here, it is demonstrated that atorvastatin decreases nuclear pAkt levels in pancreatic and lung cancer cell lines within minutes, and this rapid effect is mediated by the purinergic P2X receptors. Akt is upregulated by hepatitis viruses and has oncogenic ...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ghalali, A., Martin-Renedo, J., Högberg, J., Stenius, U. Tags: Oncogenes and Tumor Suppressors Source Type: research

Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival
Here, comprehensive analysis was performed on the molecular and clinical features of colorectal carcinoma harboring chromosome 20q amplification. Tumor and normal DNA from patients with advanced colorectal carcinoma underwent next-generation sequencing via MSK-IMPACT, and a subset of case samples was subjected to high-resolution microarray (Oncoscan). Relationships between genomic copy number and transcript expression were assessed with The Cancer Genome Atlas (TCGA) colorectal carcinoma data. Of the colorectal carcinoma patients sequenced (n = 401) with MSK-IMPACT, 148 (37%) had 20q gain, and 30 (7%) had 20q amplification...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Ptashkin, R. N., Pagan, C., Yaeger, R., Middha, S., Shia, J., O'Rourke, K. P., Berger, M. F., Wang, L., Cimera, R., Wang, J., Klimstra, D. S., Saltz, L., Ladanyi, M., Zehir, A., Hechtman, J. F. Tags: Oncogenes and Tumor Suppressors Source Type: research

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) an...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Lal, S., Cheung, E. C., Zarei, M., Preet, R., Chand, S. N., Mambelli-Lisboa, N. C., Romeo, C., Stout, M. C., Londin, E., Goetz, A., Lowder, C. Y., Nevler, A., Yeo, C. J., Campbell, P. M., Winter, J. M., Dixon, D. A., Brody, J. R. Tags: Genomics Source Type: research

Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways
This study provides novel insight into tumor-derived microvesicles as carriers of oncogenic protein–coding messages that can potentially jeopardize cell-directed therapy, and spread to other compartments of the body. Mol Cancer Res; 15(6); 683–95. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Milani, G., Lana, T., Bresolin, S., Aveic, S., Pasto, A., Frasson, C., te Kronnie, G. Tags: Genomics Source Type: research

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior
This study provides new insight into the therapeutic benefit of combining NEDD9 depletion with ROCK inhibition to reduce tumor cell dissemination and discovers a new regulatory role of NEDD9 in the modulation of VAV2-dependent activation of Rac1 and actin polymerization. Mol Cancer Res; 15(6); 670–82. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Jones, B. C., Kelley, L. C., Loskutov, Y. V., Marinak, K. M., Kozyreva, V. K., Smolkin, M. B., Pugacheva, E. N. Tags: Cell Death and Survival Source Type: research

CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC
Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand-binding specificity. It has been established that androgens induce cell-cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Thus, the efficacy of the newly d...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Stice, J. P., Wardell, S. E., Norris, J. D., Yllanes, A. P., Alley, H. M., Haney, V. O., White, H. S., Safi, R., Winter, P. S., Cocce, K. J., Kishton, R. J., Lawrence, S. A., Strum, J. C., McDonnell, D. P. Tags: Cell Death and Survival Source Type: research

The E3 Ligase CHIP Mediates p21 Degradation to Maintain Radioresistance
Lung cancer resists radiotherapy, making it one of the deadliest forms of cancer. Here, we show that human lung cancer cell lines can be rendered sensitive to ionizing radiation (IR) by RNAi knockdown of C-terminus of Hsc70-interacting protein (CHIP/STUB1), a U-box-type E3 ubiquitin ligase that targets a number of stress-induced proteins. Mechanistically, ubiquitin-dependent degradation of the cyclin-dependent kinase (CDK) inhibitor, p21 protein, is reduced by CHIP knockdown, leading to enhanced senescence of cells in response to exposure to IR. Cellular senescence and sensitivity to IR is prevented by CRISPR/Cas9-mediated...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Biswas, K., Sarkar, S., Du, K., Brautigan, D. L., Abbas, T., Larner, J. M. Tags: Cell Cycle and Senescence Source Type: research

Cancer Immunotherapy: Whence and Whither
The current concepts and practice of cancer immunotherapy evolved from classical experiments that distinguished "self" from "non-self" and the finding that humoral immunity is complemented by cellular immunity. Elucidation of the biology underlying immune checkpoints and interactions between ligands and ligand receptors that govern the immune system's ability to recognize tumor cells as foreign has led to the emergence of new strategies that mobilize the immune system to reverse this apparent tolerance. Some of these approaches have led to new therapies such as the use of mAbs to interfere with the immu...
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Authors: Stambrook, P. J., Maher, J., Farzaneh, F. Tags: Review Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

A Transcriptional Program for Detecting TGF{beta}-Induced EMT in Cancer
Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGFβ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFβ-induced EMT which can be used to score TGFβ-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumor datasets, a number of cell ...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Foroutan, M., Cursons, J., Hediyeh-Zadeh, S., Thompson, E. W., Davis, M. J. Tags: Signal Transduction Source Type: research

Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex
In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that coimmunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that C...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Rozovski, U., Harris, D. M., Li, P., Liu, Z., Jain, P., Veletic, I., Ferrajoli, A., Burger, J., O'Brien, S., Bose, P., Thompson, P., Jain, N., Wierda, W., Keating, M. J., Estrov, Z. Tags: Signal Transduction Source Type: research

Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects
TNF receptor–associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IB kinase (IKK) to regulate the NF-B and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant–negative (TRAF6dn) peptides were constructed...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Chen, H., Li, M., Sanchez, E., Wang, C. S., Lee, T., Soof, C. M., Casas, C. E., Cao, J., Xie, C., Udd, K. A., DeCorso, K., Tang, G. Y., Spektor, T. M., Berenson, J. R. Tags: Signal Transduction Source Type: research

Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis
The tumor microenvironment (TME), the dynamic tissue space in which the tumor exists, plays a significant role in tumor initiation, and is a key contributor in cancer progression; however, little is known about tumor-induced changes in the adjacent tissue stroma. Herein, tumor-induced changes in the TME were explored at the morphologic and molecular level to further understand cancer progression. Tumor-adjacent mammary glands (TAG) displayed altered branching morphology, expansion of myofibroblasts, and increased mammosphere formation, broadly suggesting a tumor-induced field effect. FACS analysis of TAGs demonstrated an i...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Zellmer, V. R., Schnepp, P. M., Fracci, S. L., Tan, X., Howe, E. N., Zhang, S. Tags: Oncogenes and Tumor Suppressors Source Type: research

Novel Assay to Detect RNA Polymerase I Activity In Vivo
This report develops an analytically validated chromogenic in situ hybridization (CISH) assay using branched DNA signal amplification (RNAscope) for detecting the expression of the 5' external transcribed spacer (ETS) of the 45S ribosomal (r) RNA precursor in formalin-fixed and paraffin-embedded (FFPE) human tissues. 5'ETS/45S CISH was performed on standard clinical specimens and tissue microarrays (TMA) from untreated prostate carcinomas, high-grade prostatic intraepithelial neoplasia (PIN), and matched benign prostatic tissues. Signals were quantified using image analysis software. The 5'ETS rRNA signal was restricted to...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Guner, G., Sirajuddin, P., Zheng, Q., Bai, B., Brodie, A., Liu, H., af Hällström, T., Kulac, I., Laiho, M., De Marzo, A. M. Tags: Metabolism Source Type: research

Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein–Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rate...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Kaymaz, Y., Oduor, C. I., Yu, H., Otieno, J. A., Ong'echa, J. M., Moormann, A. M., Bailey, J. A. Tags: Genomics Source Type: research

Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST
This study provides novel insights into the biology of quadruple WT GIST that potentially resembles neuroendocrine tumors and should promote the development of specific therapeutic approaches. Mol Cancer Res; 15(5); 553–62. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Pantaleo, M. A., Urbini, M., Indio, V., Ravegnini, G., Nannini, M., De Luca, M., Tarantino, G., Angelini, S., Gronchi, A., Vincenzi, B., Grignani, G., Colombo, C., Fumagalli, E., Gatto, L., Saponara, M., Ianni, M., Paterini, P., Santini, D., Pirini, M. G. Tags: Genomics Source Type: research

Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas
Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fib...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Laginestra, M. A., Tripodo, C., Agostinelli, C., Motta, G., Hartmann, S., Döring, C., Rossi, M., Melle, F., Sapienza, M. R., Tabanelli, V., Pileri, A., Fuligni, F., Gazzola, A., Mannu, C., Sagramoso, C. A., Lonardi, S., Lorenzi, L., Bacci, F., Sab Tags: Genomics Source Type: research

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma
In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM. Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532–40. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Schulze Heuling, E., Knab, F., Radke, J., Eskilsson, E., Martinez-Ledesma, E., Koch, A., Czabanka, M., Dieterich, C., Verhaak, R. G., Harms, C., Euskirchen, P. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155
In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant m...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Nyquist, M. D., Corella, A., Burns, J., Coleman, I., Gao, S., Tharakan, R., Riggan, L., Cai, C., Corey, E., Nelson, P. S., Mostaghel, E. A. Tags: Cell Death and Survival Source Type: research

Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression
IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell-cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Pirozzi, C. J., Carpenter, A. B., Waitkus, M. S., Wang, C. Y., Zhu, H., Hansen, L. J., Chen, L. H., Greer, P. K., Feng, J., Wang, Y., Bock, C. B., Fan, P., Spasojevic, I., McLendon, R. E., Bigner, D. D., He, Y., Yan, H. Tags: Cell Cycle and Senescence Source Type: research

Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma
Uveal melanoma is the most common primary intraocular malignant tumor in adults and arises from the transformation of melanocytes in the uveal tract. Even after treatment of the primary tumor, up to 50% of patients succumb to metastatic disease. The liver is the predominant organ of metastasis. There is an important need to provide effective treatment options for advanced stage uveal melanoma. To provide the preclinical basis for new treatments, it is important to understand the molecular underpinnings of the disease. Recent genomic studies have shown that mutations within components of G protein–coupled receptor (GP...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Chua, V., Lapadula, D., Randolph, C., Benovic, J. L., Wedegaertner, P. B., Aplin, A. E. Tags: Minireview Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Abstract A46: Nup153 and Nup50 promote recruitment of 53BP1 to DNA repair foci by antagonizing BRCA1-dependent events
This study focuses on an unexpected role for particular nuclear pore proteins in the antagonism between the DNA repair factors BRCA1 and 53BP1, and the impact this has on the response to poly(A) ribose polymerase (PARP) inhibition. Repair of DNA double strand breaks, a cornerstone of genomic integrity, typically follows one of two distinct pathways: the high fidelity process of homologous recombination (HR) repair, in which BRCA1 plays a key role, and the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in b...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mackay, D. R., Ullman, K. S. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B45: A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection
We examined the recruitment of known resection factors to DSB sites and determined that the localization of CtIP and BLM were impaired in cells depleted of ZNF335. Our data suggests that ZNF335 plays an important role in promoting resection and ATR activation in response to DSBs.Citation Format: Jordan Young, Mikhail Bashkurov, Andrea McEwan, Thomas Sun, Alessandro Datti, Daniel Durocher. A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montre...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Young, J., Bashkurov, M., McEwan, A., Sun, T., Datti, A., Durocher, D. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B44: Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer
Conclusion: Due to ERK-dependent reactivation of Akt in K-RAS mutated NSCLC cells, dual targeting of PI3K and MEK is an effective approach to induce radiosensitization.Acknowledgement: This work was supported by grants from the Deutsche Forschungsge-meinschaft (DFG, RO 527/7-1) awarded to HPR /MT and GRK 1302/2 (T11) awarded to MT/HPR.Citation Format: Mahmoud Toulany, Mari Ilda, Deric L. Wheeler, H. Peter Rodemann. Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Confe...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Toulany, M., Ilda, M., Wheeler, D. L., Rodemann, H. P. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A44: The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer
Hereditary breast cancer corresponds to 10-15% of all diagnosed cases of breast cancer in the world. The majority germline mutations are identified in BRCA1/2 genes, however the application of multigene panels has increased the number of pathogenic variations detected in DNA repair genes. According to the current version of NCCN Guideline, mutations in BRCA1/2, TP53 and PTEN confers high risk to develop breast cancer, and mutations in CDH1, CHEK2, PALB2, ATM and BRIP can increases over than 20% this risk. We analyzed 157 individuals from Northeastern region of Brazil with personal and/or familial breast cancer history. Gen...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Timoteo, A. R. d. S., Souza, J. E. S. d., Lajus, T. B. P. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B43: RECQ1, a breast cancer susceptibility gene, is upregulated by cancer therapeutics in a p53-dependent manner
Sensitivity of cancer cells to DNA-damaging chemotherapeutics is determined by DNA repair processes. Consequently, cancer cells may upregulate expression of certain DNA repair genes as a mechanism to promote chemoresistance. Here, we report identification of RECQ1, a breast cancer susceptibility gene that encodes the most abundant RecQ helicase in humans, as a p53-regulated target potentially acting as a defense against DNA-damaging agents. Quantitative RT-PCR analysis in a variety of cancer cell lines revealed RECQ1 to be upregulated following DNA damage, which was confirmed by Western blot experiments. Significant increa...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lu, X., Parvathaneni, S., Sharma, S. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A43: TFG-TEC oncogene modulates beta-enolase expression via both promoter activation and epigenetic modification
Recurrent chromosome translocations are the hallmark of many human cancers. A proportion of human extraskeletal myxoid chondrosarcomas (EMCs) are associated with the characteristic chromosomal translocation t(3;9)(q11-12;q22), which results in the formation of a chimeric protein in which the N-terminal domain of the TRK-fused gene (TFG) is fused to the translocated in extraskeletal chondrosarcoma (TEC; also called CHN, CSMF, MINOR, NOR1, and NR4A3) gene. The oncogenic effect of this translocation may be due to the higher transactivation ability of the TFG-TEC chimeric protein; however, downstream target genes of TFG-TEC ha...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Kim, A.-y., Lim, B., Choi, J., Kim, J. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A42: Identification of glutamate and aspartate ADP-ribosylation sites onto histones by mass mass spectrometry
Chromatin structure and function is regulated by histone post-translational modifications. Histone proteins are subject to a variety of post-translational modifications that can work combinatorially to alter the transcriptional state or the repair of DNA damage. The landscape of histone modifications includes mono- and poly(ADP-ribosylation), which can directly alter nucleosome structure and DNA accessibility. ADP-ribosylation occuring on glutamate and aspartate residues was the most intensively studied histone ADP-ribosylation modification in the past, primarily because these carboxylester-type ADP-ribose–protein bo...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Gagne, J.-P., Roux-Dalvai, F., Defoy, D., Droit, A., Michael, H. J., Poirier, G. G. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B41: REV7 is a possible prognostic predictor and a potential therapeutic target in human malignancy
Human REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene transcription and carcinogenesis, and is a key protein in translesion DNA synthesis. Here, we present our study to evaluate the significance of REV7 expression in human malignancy and its possibility to be a molecular target for cancer therapy. REV7 expression was assessed in epithelial ovarian cancer (EOC) and diffuse large B-cell lymphoma (DLBCL) by immunohistochemical staining. REV7 expression was detected in the majority of EOCs (92.0%) with especially high levels of expression frequently observed in ovarian clear cell ca...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Murakumo, Y., Niimi, K., Okina, S. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research