Pathology-Driven Comprehensive Proteomic Profiling of the Prostate Cancer Tumor Microenvironment
This report undertook a detailed molecular characterization of the tumor microenvironment in prostate cancer to define the proteome in the epithelial and stromal regions from tumor foci of Gleason grades 3 and 4. Tissue regions of interest were isolated from several Gleason 3+3 and Gleason 4+4 tumors using telepathology to leverage specialized pathology expertise to support LCM. Over 2,000 proteins were identified following liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of all regions of interest. Statistical analysis revealed significant differences in protein expression (>100 proteins) between Glea...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Staunton, L., Tonry, C., Lis, R., Espina, V., Liotta, L., Inzitari, R., Bowden, M., Fabre, A., O'Leary, J., Finn, S. P., Loda, M., Pennington, S. R. Tags: Genomics Source Type: research
DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy
Resistance to cancer chemotherapies leads to deadly consequences, yet current research focuses only on the roles of somatically acquired mutations in this resistance. The mutational status of the germline is also likely to play a role in the way cells respond to chemotherapy. The carrier status for the POLB rs3136797 germline mutation encoding P242R DNA polymerase beta (Pol β) is associated with poor prognosis for lung cancer, specifically in response to treatment with cisplatin. Here, it is revealed that the P242R mutation is sufficient to promote resistance to cisplatin in human cells and in mouse xenografts. Mechan...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Nemec, A. A., Abriola, L., Merkel, J. S., de Stanchina, E., DeVeaux, M., Zelterman, D., Glazer, P. M., Sweasy, J. B. Tags: DNA Damage and Repair Source Type: research
Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Williams, M. M., Lee, L., Hicks, D. J., Joly, M. M., Elion, D., Rahman, B., McKernan, C., Sanchez, V., Balko, J. M., Stricker, T., Estrada, M. V., Cook, R. S. Tags: Cell Death and Survival Source Type: research
Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma
This study shows that autophagy inhibition enhances sunitinib-mediated cell death in a preclinical model of CCOC. Mol Cancer Res; 15(3); 250–8. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: DeVorkin, L., Hattersley, M., Kim, P., Ries, J., Spowart, J., Anglesio, M. S., Levi, S. M., Huntsman, D. G., Amaravadi, R. K., Winkler, J. D., Tinker, A. V., Lum, J. J. Tags: Cell Death and Survival Source Type: research
Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth
Senescent cells within the tumor microenvironment (TME) adopt a proinflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression, and therapeutic resistance. Here, exposure to palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage–independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-B activation. Based upon these observations, it was hypothesized that the exposure of nontransformed stromal cel...
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: Guan, X., LaPak, K. M., Hennessey, R. C., Yu, C. Y., Shakya, R., Zhang, J., Burd, C. E. Tags: Cell Cycle and Senescence Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Astrocyte Elevated Gene-1 Regulates {beta}-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal
This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225–33. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Hu, B., Emdad, L., Kegelman, T. P., Shen, X.-N., Das, S. K., Sarkar, D., Fisher, P. B. Tags: Signal Transduction Source Type: research
MYC Mediates mRNA Cap Methylation of Canonical Wnt/{beta}-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase
MYC is a pleiotropic transcription factor that activates and represses a wide range of target genes and is frequently deregulated in human tumors. While much is known about the role of MYC in transcriptional activation and repression, MYC can also regulate mRNA cap methylation through a mechanism that has remained poorly understood. Here, it is reported that MYC enhances mRNA cap methylation of transcripts globally, specifically increasing mRNA cap methylation of genes involved in Wnt/β-catenin signaling. Elevated mRNA cap methylation of Wnt signaling transcripts in response to MYC leads to augmented translational cap...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Posternak, V., Ung, M. H., Cheng, C., Cole, M. D. Tags: Oncogenes and Tumor Suppressors Source Type: research
Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with the 5-year survival rate less than 6%. Previous results indicated that serum levels of CA125 (encoded by MUC16) could be used to predict which groups of pancreatic cancer patients may benefit from surgery. However, the underlying mechanism remains elusive. Herein, using the Cancer Genome Atlas and clinicopathologic data obtained from our center, we demonstrate that high CA125 serum levels and expression levels of MUC16 are predictive of poor prognosis. MUC16 is also validated as a downstream target of KRAS, and their expression strongly correlated with e...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Liang, C., Qin, Y., Zhang, B., Ji, S., Shi, S., Xu, W., Liu, J., Xiang, J., Liang, D., Hu, Q., Ni, Q., Xu, J., Yu, X. Tags: Oncogenes and Tumor Suppressors Source Type: research
Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype
Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration, and survival in many cell types. Here, the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: noninvasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quanti...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Ashkavand, Z., O'Flanagan, C., Hennig, M., Du, X., Hursting, S. D., Krupenko, S. A. Tags: Metabolism Source Type: research
High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV
In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positiv...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Walline, H. M., Carey, T. E., Goudsmit, C. M., Bellile, E. L., D'Souza, G., Peterson, L. A., McHugh, J. B., Pai, S. I., Lee, J. J., Shin, D. M., Ferris, R. L., on behalf of the HNC SPORE HIV supplement consortium Tags: Genomics Source Type: research
Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis
Lipolysis-stimulated lipoprotein receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. C...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Reaves, D. K., Hoadley, K. A., Fagan-Solis, K. D., Jima, D. D., Bereman, M., Thorpe, L., Hicks, J., McDonald, D., Troester, M. A., Perou, C. M., Fleming, J. M. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research
A New Role for ER{alpha}: Silencing via DNA Methylation of Basal, Stem Cell, and EMT Genes
Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α–positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+ cells but derepressed upon exposure to t...
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Ariazi, E. A., Taylor, J. C., Black, M. A., Nicolas, E., Slifker, M. J., Azzam, D. J., Boyd, J. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research
Combined Parthenolide and Balsalazide Have Enhanced Antitumor Efficacy Through Blockade of NF-{kappa}B Activation
This study represents the first evidence that combination therapy with balsalazide and parthenolide could be a new regimen for colorectal cancer treatment. Mol Cancer Res; 15(2); 141–51. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Kim, S.-L., Kim, S. H., Park, Y. R., Liu, Y.-C., Kim, E.-M., Jeong, H.-J., Kim, Y. N., Seo, S. Y., Kim, I. H., Lee, S. O., Lee, S. T., Kim, S.-W. Tags: Cell Death and Survival Source Type: research
The Efflux Transporter ABCG2 Maintains Prostate Stem Cells
This study identifies the mechanism by which the prostate stem cell marker, ABCG2, plays a role in prostate stem cell maintenance and provides a rationale for targeting ABCG2 for differentiation therapy in prostate cancer. Mol Cancer Res; 15(2); 128–40. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Sabnis, N. G., Miller, A., Titus, M. A., Huss, W. J. Tags: Cell Death and Survival Source Type: research
