CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKK{alpha}
Previously, we identified the transcriptional coactivator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models. While CIT...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Jayaraman, S., Doucet, M., Lau, W. M., Kominsky, S. L. Tags: Oncogenes and Tumor Suppressors Source Type: research

An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma
Vulvar squamous cell carcinoma (VSCC) is a rare disease that has a high mortality rate (~40%). However, little is known about its molecular signature. Therefore, an integrated genomics approach, based on comparative genome hybridization (aCGH) and genome-wide expression (GWE) array, was performed to identify driver genes in VSCC. To achieve that, DNA and RNA were extracted from frozen VSCC clinical specimens and examined by aCGH and GWE array, respectively. On the basis of the integration of data using the CONEXIC algorithm, PLXDC2 and GNB3 were validated by RT-qPCR. The expression of these genes was then analyzed by IHC i...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Lavorato-Rocha, A. M., Akagi, E. M., de Melo Maia, B., Rodrigues, I. S., Botelho, M. C. S., Marchi, F. A., Fernandes, G., Baiocchi, G., Soares, F. A., Rogatto, S. R., Sato-Kuwabara, Y., Rocha, R. M. Tags: Genomics Source Type: research

GR and ER Coactivation Alters the Expression of Differentiation Genes and Associates with Improved ER+ Breast Cancer Outcome
In estrogen receptor (ER)–negative breast cancer, high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a meta-analysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapse-free survival (RFS; independently of progesterone receptor expression). To understand the mechanism by which GR expression is associated with a better ER+ breast cancer outcome, the global effect of GR-mediated transcriptional activation in ER+ breast cancer cells was studied. Analysis of GR chromatin immunoprecipitation f...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: West, D. C., Pan, D., Tonsing-Carter, E. Y., Hernandez, K. M., Pierce, C. F., Styke, S. C., Bowie, K. R., Garcia, T. I., Kocherginsky, M., Conzen, S. D. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Role for the Aryl Hydrocarbon Receptor and Diverse Ligands in Oral Squamous Cell Carcinoma Migration and Tumorigenesis
This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro. Mol Cancer Res; 14(8); 696–706. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Stanford, E. A., Ramirez-Cardenas, A., Wang, Z., Novikov, O., Alamoud, K., Koutrakis, P., Mizgerd, J. P., Genco, C. A., Kukuruzinska, M., Monti, S., Bais, M. V., Sherr, D. H. Tags: Cell Death and Survival Source Type: research

AMPK Causes Cell Cycle Arrest in LKB1-Deficient Cells via Activation of CAMKK2
The AMP-activated protein kinase (AMPK) is activated by phosphorylation at Thr172, either by the tumor suppressor kinase LKB1 or by an alternate pathway involving the Ca2+/calmodulin-dependent kinase, CAMKK2. Increases in AMP:ATP and ADP:ATP ratios, signifying energy deficit, promote allosteric activation and net Thr172 phosphorylation mediated by LKB1, so that the LKB1–AMPK pathway acts as an energy sensor. Many tumor cells carry loss-of-function mutations in the STK11 gene encoding LKB1, but LKB1 reexpression in these cells causes cell-cycle arrest. Therefore, it was investigated as to whether arrest by LKB1 is cau...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Fogarty, S., Ross, F. A., Vara Ciruelos, D., Gray, A., Gowans, G. J., Hardie, D. G. Tags: Cell Cycle and Senescence Source Type: research

Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance
This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and bio...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: The Cancer Target Discovery and Development Network Tags: Perspective Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Tags: Perspective Highlights Source Type: research

JNK1 Inhibition Potentiates Chemotherapy
Inhibition of hypoxia-induced stress signaling through JNK potentiates the effects of oxaliplatin. The JNK pathway plays a role in both autophagy and apoptosis; therefore, it was determined how much of the effect of JNK inhibition on oxaliplatin sensitivity is dependent on its effect on autophagy. We studied the impact of JNK isoform downregulation in the HT29 colon adenocarcinoma cell line on hypoxia- and oxaliplatin-induced responses. Electron microscopic analyses demonstrated that both oxaliplatin- and hypoxia-induced formations of autophagosomes were reduced significantly in HT29 cells treated with the JNK inhibitor SP...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Vasilevskaya, I. A., Selvakumaran, M., Roberts, D., O'Dwyer, P. J. Tags: Signal Transduction Source Type: research

EGFR Mutations in Neuroblastoma
In conclusion, this is the first study to demonstrate that neuroblastoma express not only EGFRvIII, but also a novel EGFR extracellular domain deletion mutant, EGFR768. The EGFR768 also possesses distinct biologic and biochemical properties which might have therapeutic implications for neuroblastoma as well as other tumors expressing this novel mutant. Implications: Neuroblastoma expressed a novel EGFR mutant which possesses distinct biologic and biochemical properties that might have therapeutic implications. Mol Cancer Res; 14(8); 740–52. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Keller, J., Nimnual, A. S., Varghese, M. S., VanHeyst, K. A., Hayman, M. J., Chan, E. L. Tags: Oncogenes and Tumor Suppressors Source Type: research

CITED2 Modulates Human Breast Cancer Metastasis
Previously, we identified the transcriptional coactivator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models. While CIT...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Jayaraman, S., Doucet, M., Lau, W. M., Kominsky, S. L. Tags: Oncogenes and Tumor Suppressors Source Type: research

New Tumor Markers for Vulvar Carcinoma
Vulvar squamous cell carcinoma (VSCC) is a rare disease that has a high mortality rate (~40%). However, little is known about its molecular signature. Therefore, an integrated genomics approach, based on comparative genome hybridization (aCGH) and genome-wide expression (GWE) array, was performed to identify driver genes in VSCC. To achieve that, DNA and RNA were extracted from frozen VSCC clinical specimens and examined by aCGH and GWE array, respectively. On the basis of the integration of data using the CONEXIC algorithm, PLXDC2 and GNB3 were validated by RT-qPCR. The expression of these genes was then analyzed by IHC i...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Lavorato-Rocha, A. M., Akagi, E. M., de Melo Maia, B., Rodrigues, I. S., Botelho, M. C. S., Marchi, F. A., Fernandes, G., Baiocchi, G., Soares, F. A., Rogatto, S. R., Sato-Kuwabara, Y., Rocha, R. M. Tags: Genomics Source Type: research

GR and ER Increase Expression of Differentiation Genes
In estrogen receptor (ER)–negative breast cancer, high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a meta-analysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapse-free survival (RFS; independently of progesterone receptor expression). To understand the mechanism by which GR expression is associated with a better ER+ breast cancer outcome, the global effect of GR-mediated transcriptional activation in ER+ breast cancer cells was studied. Analysis of GR chromatin immunoprecipitation f...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: West, D. C., Pan, D., Tonsing-Carter, E. Y., Hernandez, K. M., Pierce, C. F., Styke, S. C., Bowie, K. R., Garcia, T. I., Kocherginsky, M., Conzen, S. D. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Role of the AhR in Oral Cancer Migration and Tumorigenesis
This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro. Mol Cancer Res; 14(8); 696–706. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Stanford, E. A., Ramirez-Cardenas, A., Wang, Z., Novikov, O., Alamoud, K., Koutrakis, P., Mizgerd, J. P., Genco, C. A., Kukuruzinska, M., Monti, S., Bais, M. V., Sherr, D. H. Tags: Cell Death and Survival Source Type: research

AMPK Causes G1 Arrest in LKB1-Null Cells by CAMKK2 Pathway
The AMP-activated protein kinase (AMPK) is activated by phosphorylation at Thr172, either by the tumor suppressor kinase LKB1 or by an alternate pathway involving the Ca2+/calmodulin-dependent kinase, CAMKK2. Increases in AMP:ATP and ADP:ATP ratios, signifying energy deficit, promote allosteric activation and net Thr172 phosphorylation mediated by LKB1, so that the LKB1–AMPK pathway acts as an energy sensor. Many tumor cells carry loss-of-function mutations in the STK11 gene encoding LKB1, but LKB1 reexpression in these cells causes cell-cycle arrest. Therefore, it was investigated as to whether arrest by LKB1 is cau...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: Fogarty, S., Ross, F. A., Vara Ciruelos, D., Gray, A., Gowans, G. J., Hardie, D. G. Tags: Cell Cycle and Senescence Source Type: research

Reproducibility of Big Data Translation: Cancer Discoveries
This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and bio...
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Authors: The Cancer Target Discovery and Development Network Tags: Perspective Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - August 13, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

The Effect of Adipose Stem Cells on Breast Cancer
This study focused on delineating the effects of ASCs and adipocytes on the self-renewal of stem/progenitor cells and hierarchy of breast epithelial cells. The immortalized breast epithelial cell line MCF10A, ductal carcinoma in situ (DCIS) cell lines MCF10DCIS.com and SUM225, and MCF10A-overexpressing SRC oncogene were examined using a mammosphere assay and flow cytometry for the effects of ASCs on their self-renewal and stem-luminal progenitor-differentiated cell surface marker profiles. Interestingly, ASCs promoted the self-renewal of all cell types except SUM225. ASC coculture or treatment with ASC conditioned media al...
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: Anjanappa, M., Burnett, R., Zieger, M. A., Merfeld-Clauss, S., Wooden, W., March, K., Tholpady, S., Nakshatri, H. Tags: Signal Transduction Source Type: research

Noncanonical WNT5A-ROR2 Axis in Esophageal Adenocarcinoma
In this study, we aimed to determine the role of WNT5A/ROR2 signaling in esophageal adenocarcinoma. Analysis of WNT5A and ROR2 expression patterns in healthy controls, Barrett and esophageal adenocarcinoma patients' esophageal clinical specimens as well as in various esophageal cell lines demonstrated a ROR2 overexpression in esophageal adenocarcinoma tissues compared with Barrett and healthy mucosa, whereas WNT5A expression was found significantly downregulated toward esophageal adenocarcinoma formation. Treatment of esophageal adenocarcinoma OE33 cells with human recombinant WNT5A (rhWNT5A) significantly suppressed proli...
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: Lyros, O., Nie, L., Moore, T., Medda, R., Otterson, M., Behmaram, B., Mackinnon, A., Gockel, I., Shaker, R., Rafiee, P. Tags: Signal Transduction Source Type: research

HNRNP E1 Posttranscriptionally Regulates CDC27 Expression
CDC27 is a core component of the anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase, whose oscillatory activity is responsible for the metaphase-to-anaphase transition and mitotic exit. Here, in normal murine mammary gland epithelial cells (NMuMG), CDC27 expression is controlled posttranscriptionally through the RNA binding protein poly(rC) binding protein 1 (PCBP1)/heterogeneous nuclear ribonucleoprotein E1 (HNRNP E1). shRNA-mediated knockdown of HNRNP E1 abrogates translational silencing of the Cdc27 transcript, resulting in constitutive expression of CDC27. Dysregulated expression of CDC27 ...
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: Link, L. A., Howley, B. V., Hussey, G. S., Howe, P. H. Tags: Oncogenes and Tumor Suppressors Source Type: research

ANRIL Deregulation in Breast Cancer
This study suggests that the global pattern of expression rather than expression of individual family members should be taken into account when defining functionality of repressive Polycomb complexes and therapeutic targeting potential. Mol Cancer Res; 14(7); 623–33. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: Meseure, D., Vacher, S., Alsibai, K. D., Nicolas, A., Chemlali, W., Caly, M., Lidereau, R., Pasmant, E., Callens, C., Bieche, I. Tags: Genomics Source Type: research

DNA Repair Inhibition by Oxidative Stress
The relationship between sun exposure and nonmelanoma skin cancer risk is well established. Solar UV (wavelength 280–400 nm) is firmly implicated in skin cancer development. Nucleotide excision repair (NER) protects against cancer by removing potentially mutagenic DNA lesions induced by UVB (280–320 nm). How the 20-fold more abundant UVA (320–400 nm) component of solar UV radiation increases skin cancer risk is not understood. Here it is demonstrated that the contribution of UVA to the effect of UV radiation on cultured human cells is largely independent of its ability to damage DNA. Instead, the effects ...
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: McAdam, E., Brem, R., Karran, P. Tags: DNA Damage and Repair Source Type: research

HuR Mediates TRAIL Resistance
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. TRAIL directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-...
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: Romeo, C., Weber, M. C., Zarei, M., DeCicco, D., Chand, S. N., Lobo, A. D., Winter, J. M., Sawicki, J. A., Sachs, J. N., Meisner-Kober, N., Yeo, C. J., Vadigepalli, R., Tykocinski, M. L., Brody, J. R. Tags: Cell Death and Survival Source Type: research

The Renal Cell Carcinomas
In conclusion, this review summarizes RCCs that represent a diverse set of malignancies, each with novel biologic programs that define new paradigms for cancer biology. Mol Cancer Res; 14(7); 589–98. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: Haake, S. M., Weyandt, J. D., Rathmell, W. K. Tags: Review Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

SOCS3 and Androgen Receptor Signaling in Prostate Cancer
This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor–positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor–mediated sup...
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Authors: Handle, F., Erb, H. H. H., Luef, B., Hoefer, J., Dietrich, D., Parson, W., Kristiansen, G., Santer, F. R., Culig, Z. Tags: Signal Transduction Source Type: research

Oncogenic and Tumor Suppressor Roles of PTK6 in Colon Cancer
Disruption of the gene encoding Protein Tyrosine Kinase 6 (Ptk6) delayed differentiation and increased growth in the mouse intestine. However, Ptk6-null mice were also resistant to azoxymethane-induced colon tumorigenesis. To further explore functions of PTK6 in colon cancer, expression of epithelial and mesenchymal markers, as well as proliferation, migration, and xenograft tumor growth, was examined in human colon tumor cell lines with knockdown or overexpression of PTK6. PTK6 protein, transcript, and activation were also examined in a human colon tumor tissue array, using immunohistochemistry and qRT-PCR. Knockdown of P...
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Authors: Mathur, P. S., Gierut, J. J., Guzman, G., Xie, H., Xicola, R. M., Llor, X., Chastkofsky, M. I., Perekatt, A. O., Tyner, A. L. Tags: Signal Transduction Source Type: research

Dual Role of miR-146a in Tumor Progression
This study reconciles the contradictory biologic functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions. Implications: miR-146a controls melanoma progression in a dual way, promoting growth and inhibiting dissemination; however, it is poorly expressed in CTCs, resulting in overall tumor spreading and distant-site colonization. Mol Cancer Res; 14(6); 548–62. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Authors: Raimo, M., Orso, F., Grassi, E., Cimino, D., Penna, E., De Pitta, C., Stadler, M. B., Primo, L., Calautti, E., Quaglino, P., Provero, P., Taverna, D. Tags: Oncogenes and Tumor Suppressors Source Type: research

c-MET CTC Platform for GI and GU Malignancies
This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539–47. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Authors: Zhang, T., Boominathan, R., Foulk, B., Rao, C., Kemeny, G., Strickler, J. H., Abbruzzese, J. L., Harrison, M. R., Hsu, D. S., Healy, P., Li, J., Pi, C., Prendergast, K. M., Hobbs, C., Gemberling, S., George, D. J., Hurwitz, H. I., Connelly, M., Garcia-Bla Tags: Oncogenes and Tumor Suppressors Source Type: research

GRHL2 Suppresses GLUD1 Sensitizing to Anoikis
Resistance to anoikis is a prerequisite for tumor metastasis. The epithelial-to-mesenchymal transition (EMT) allows tumor cells to evade anoikis. The wound-healing regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses/reverses EMT, accompanied by suppression of the cancer stem cell (CSC) phenotype and by resensitization to anoikis. Here, the effects of GRHL2 upon intracellular metabolism in the context of reversion of the EMT/CSC phenotype, with a view toward understanding how these effects promote anoikis sensitivity, were investigated. EMT enhanced mitochondrial oxidative metabolism. Although this was acco...
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Authors: Farris, J. C., Pifer, P. M., Zheng, L., Gottlieb, E., Denvir, J., Frisch, S. M. Tags: Cell Death and Survival Source Type: research

Targeting CX3CR1 Reduces Breast Cancer Metastasis
In conclusion, these data support the drug development of CX3CR1 antagonists, and promoting their clinical use will provide novel and effective tools to prevent or contain the progression of metastatic disease in breast cancer patients. Implications: This work conclusively validates the instrumental role of CX3CR1 in the seeding of circulating cancer cells and is expected to pave the way for pairing novel inhibitors of this receptor with current standards of care for the treatment of breast cancer patients. Mol Cancer Res; 14(6); 518–27. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Authors: Shen, F., Zhang, Y., Jernigan, D. L., Feng, X., Yan, J., Garcia, F. U., Meucci, O., Salvino, J. M., Fatatis, A. Tags: Cell Death and Survival Source Type: research

APA in Cancer
Advancements in sequencing and transcriptome analysis methods have led to seminal discoveries that have begun to unravel the complexity of cancer. These studies are paving the way toward the development of improved diagnostics, prognostic predictions, and targeted treatment options. However, it is clear that pieces of the cancer puzzle are still missing. In an effort to have a more comprehensive understanding of the development and progression of cancer, we have come to appreciate the value of the noncoding regions of our genomes, partly due to the discovery of miRNAs and their significance in gene regulation. Interestingl...
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Authors: Erson-Bensan, A. E., Can, T. Tags: Review Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - June 14, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

{beta}-Arrestin-2 Regulates EGFR Transactivation
This study reveals that β-AR2 functions as a tumor suppressor, underscoring its clinical importance in regulating CXCR7/EGFR–mediated tumor cell proliferation. Mol Cancer Res; 14(5); 493–503. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Kallifatidis, G., Munoz, D., Singh, R. K., Salazar, N., Hoy, J. J., Lokeshwar, B. L. Tags: Signal Transduction Source Type: research

Basal ISG Expression Diminishes oHSV Productivity
Interferon-stimulated genes (ISG) encode diverse proteins that mediate intrinsic antiviral resistance in infected cells. Here it was hypothesized that malignant peripheral nerve sheath tumor (MPNST) cells resist the productive infection of oncolytic herpes simplex virus (oHSV) through activation of the JAK/STAT1 pathway and resultant upregulation of ISGs. Multiple human and mouse MPNST cells were used to explore the relationship between STAT1 activation and the productive infection of 134.5 oHSVs. STAT1 activation in response to oHSV infection was found to associate with diminished 134.5 oHSVs replication and spread. Multi...
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Jackson, J. D., Markert, J. M., Li, L., Carroll, S. L., Cassady, K. A. Tags: Signal Transduction Source Type: research

AP-1 and Endocrine Resistance
In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo. AP-1 ...
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Malorni, L., Giuliano, M., Migliaccio, I., Wang, T., Creighton, C. J., Lupien, M., Fu, X., Hilsenbeck, S. G., Healy, N., De Angelis, C., Mazumdar, A., Trivedi, M. V., Massarweh, S., Gutierrez, C., De Placido, S., Jeselsohn, R., Brown, M., Brown, P. H., Os Tags: Oncogenes and Tumor Suppressors Source Type: research

Tyrosine Phosphorylation of FGFR3-TACC3
Fibroblast growth factor receptors (FGFR) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the detection of FGFR translocations and fusion proteins. The research conducted in this article examines a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3), frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcin...
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Nelson, K. N., Meyer, A. N., Siari, A., Campos, A. R., Motamedchaboki, K., Donoghue, D. J. Tags: Oncogenes and Tumor Suppressors Source Type: research

EGFR and DEPTOR in Lung Cancer Progression
This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth. Implications: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression. Mol Cancer Res; 14(5); 448–57. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Zhou, X., Guo, J., Ji, Y., Pan, G., Liu, T., Zhu, H., Zhao, J. Tags: Oncogenes and Tumor Suppressors Source Type: research

Chemo-Treated Pancreatic CAFs Are Protumorigenic
This study aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAF) were generated by continuous incubation in gemcitabine. Gene expression differences between treatment-naìˆve CAFs (N-CAF) and R-CAFs were compared by array analysis. Functionally, tumor cells (TC) were exposed to N-CAF– or R-CAF–conditioned media and assayed for migration, invasion, and viability in vitro. Furthermore, a coinjection (TC and CAF) model was used to compare tumor growth in vivo. R-CAFs increased TC viability, migration, and...
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Toste, P. A., Nguyen, A. H., Kadera, B. E., Duong, M., Wu, N., Gawlas, I., Tran, L. M., Bikhchandani, M., Li, L., Patel, S. G., Dawson, D. W., Donahue, T. R. Tags: Genomics Source Type: research

Checkpoint-Mediated Accumulation of Mutant p53
Many mutant p53 proteins exhibit an abnormally long half-life and overall increased abundance compared with wild-type p53 in tumors, contributing to mutant p53's gain-of-function oncogenic properties. Here, a novel mechanism is revealed for the maintenance of mutant p53 abundance in cancer that is dependent on DNA damage checkpoint activation. High-level mutant p53 expression in lung cancer cells was associated with preferential p53 monoubiquitination versus polyubiquitination, suggesting a role for the ubiquitin/proteasome system in regulation of mutant p53 abundance in cancer cells. Interestingly, mutant p53 ubiquitinati...
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Frum, R. A., Love, I. M., Damle, P. K., Mukhopadhyay, N. D., Palit Deb, S., Deb, S., Grossman, S. R. Tags: DNA Damage and Repair Source Type: research

The Role of MAML3 in Neuroblastoma
Neuroblastoma cell lines can differentiate upon treatment with retinoic acid (RA), a finding that provided the basis for the clinical use of RA to treat neuroblastoma. However, resistance to RA is often observed, which limits its clinical utility. Using a gain-of-function genetic screen, we identified an unexpected link between RA signaling and mastermind-like 3 (MAML3), a known transcriptional coactivator for NOTCH. Our findings indicate that MAML3 expression leads to the loss of activation of a subset of RA target genes, which hampers RA-induced differentiation and promotes resistance to RA. The regulatory DNA elements o...
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Heynen, G. J. J. E., Nevedomskaya, E., Palit, S., Jagalur Basheer, N., Lieftink, C., Schlicker, A., Zwart, W., Bernards, R., Bajpe, P. K. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Abstract B40: Effect of Sasa quelpaertensis leaf extracts on the gut microbiota in dextran sodium sulfate-induced colitis in mice
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are chronic inflammatory disorders of gastrointestinal tract. Although the etiology of IBD is not clear, it may be associated with genetics and lifestyle factors, diet and gut microbiome. In particular, the imbalance among the immune system and gut microbiota and diet may play a key role in developing IBD. Sasa quelpaertensis leaves have shown anti-inflammatory and anticarcinogenic effects, although the effect of these leaves on gut microbiota in colitis remains unclear. The present study hypothesized that Sasa quelpaertensis leaves ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Yeom, Y., Kim, Y. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B38: Quiescence as a marker of treatment resistance and malignancy in GBM
Glioblastoma multiforme (GBM) is a World Health Organization grade IV astrocytic tumor, and is the most common primary brain malignancy. GBM is characterized as being highly malignant and rapidly progressive with a high mitotic index, diffuse invasion, microvascular proliferation and pseudopalisading necrosis. Current best treatment for GBM involves maximal safe surgical resection, with radiotherapy (XRT) and temozolomide (TMZ), but even with this regime patients survive for an average of only ~15 months. GBM’s position within the brain and diffuse progression profile prevents a surgical cure, and the cells left behi...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Atkins, R. J., Stylli, S. S., Luwor, R. B., Ware, T. M., Kaye, A. H., Hovens, C. M. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A38: In vitro and in vivo interaction of Cdk6 and Eya2 indicate potential crosstalk
We have identified a novel association of the developmentally significant protein, Eya2, with cyclin dependent kinase (cdk) 6. Eya2 is part of the conserved retinal determination network that has been shown to function in fly eye development (Rebay, 2005). In mammals, the EYA gene product has been implicated in gonadogenesis, myogenesis, neurognenesis, limb formation, thymus, and kidney development, in part through its ability to regulate cell proliferation (Zhang 2005). Eya2 is overexpressed in several types of cancers including epithelial ovarian (Zhang et al, 2005), cervical (Bierkens et al, 2013), lung adenocarcinoma (...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Kohrt, D., Hinds, P., Ford, H., Grossel, M. Tags: Signaling Pathways: Notch: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B37: hnRNP K in acute promyelocytic leukemia cells NB4 and NB4-R2: Involvement in cell survival and differentiation
hnRNP K has been reported to be overexpressed in myeloid leukemia and it is downregulated during all-trans retinoic acid (ATRA) induced differentiation of Acute Promyelocytic Leukemia (APL) cells. The aim of the present study was to establish role of hnRNP K in APL using responsive (NB4) and resistant (NB4-R2) cells to the all-trans retinoic acid treatment as well as the possible role of hnRNPK in ATRA-induced cellular differentiation. After demonstration, by Western blotting analysis, that hnRNP K is overexpressed (10 fold) in APL (NB4 and NB4-R2) cell lines compared to controls (bone marrow and polymorphonuclear cells), ...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Padovani, K. S., Annichini, M. S. B., Rego, E. M., Curti, C., Greene, L. J., Leopoldino, A. M. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A37: Tumor heterogeneity in SCLC: A role for endogenous Notch signaling
In conclusion, Notch is a potent suppressor of SCLC. However, Notch may have pro-tumorigenic effects in SCLC, possibly under stress conditions. A better understanding of the molecular and cellular roles of Notch is required before therapeutic strategies manipulating the Notch pathway can be used in SCLC patients.Citation Format: Jing Shan Lim, Alvaro Ibaseta, Dian Yang, Nadine S. Jahchan, Julien Sage. Tumor heterogeneity in SCLC: A role for endogenous Notch signaling. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Ca...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Lim, J. S., Ibaseta, A., Yang, D., Jahchan, N. S., Sage, J. Tags: Signaling Pathways: Notch: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B36: RENCA macrobead-induced AKT hyperphosphorylation leads to MEF2 activation and inhibition of the proliferation of human DU145 prostate carcinoma cells
We have previously reported that suppression of the isoforms of myocyte enhancer factor (MEF2) in target tumor cells in vitro reduces the demonstrated proliferation-inhibitory effect of agarose-agarose encapsulated mouse renal adenocarcinoma cells (RENCA macrobeads), suggesting that it is a critical component of a pathway by which the inhibitory action, now being evaluated also in Phase IIb human clinical trials, is mediated. Importantly, MEF2 originally described as active in myogenesis, has been found to be a key regulator of many developmental pathways and to have both pro- and anti-growth regulatory functions in murine...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Martis, P. C., Laramore, M. A., Dudley, A. T., Smith, B. H., Gazda, L. S. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A36: Notch signaling promotes tumor metastasis in the Pten null mouse model for prostate cancer
The role of Notch signaling in prostate cancer remains inconclusive. We show that a higher Notch signature score is significantly correlated with higher disease grade, metastatic potential and higher probability of lethal outcome in two published human prostate cancer datasets. We employ genetic approaches to investigate the role of Notch signaling in initiation and progression of prostate cancer in a Pten null mouse model. Notch signaling is dispensable for disease initiation and progression in this model. Elevated Notch activity in the Pten null model promotes both epithelial proliferation and apoptosis, which collective...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Kwon, O.-J., Zhang, L., Jianghua, W., Creighton, C., Ittmann, M., Xin, L. Tags: Signaling Pathways: Notch: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B34: A novel role for {beta}-adrenergic receptor in mammary branching morphogenesis and its implication in breast cancer
The mammary gland develops from embryogenesis to infancy-puberty and adulthood, by the input of circulating hormones. At birth the gland is composed of a rudimentary ductal system that grows allometrically until puberty (4-weeks in mice). Later on, estrogens, growth hormone and insulin like growth factor induce expansive proliferation. Normal breast has three types of lobules, type 1, 2 and 3. Full term pregnancy and lactation results in the development of lobule type 3 into type 4, preparing the gland for lactation. This transformation is known to inhibit carcinogenic initiation through the induction of differentiation.&b...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: May, M., Rivero, E. M., John, L., Lamb, C., Lanari, C., Luthy, I. A., Bruzzone, A. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA33: Regulation of TGF-{beta} receptor signaling in cancer
TGF-β plays a crucial role during development and in maintaining tissue homeostasis. Perturbation in signaling via TGF-β type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors, can lead to a large variety of diseases, including cancer. TGF-β has a dual role in cancer progression. During the early phase, TGF-β acts as a tumor suppressor, exemplified by deletions or mutations in the core components of the TGF-β signaling pathway. In late phase, TGF-β promotes processes that support tumor progression such as tumor cell invasion, dissemination, and im...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Dijke, P. t. Tags: Signaling Pathways: BMP/TGFbeta/SMAD: Oral Presentations - Invited Abstracts Source Type: research