Abstract A04: Phosphorylation and ubiquitylation on the RPA-ssDNA platform promote homologous recombination
Replication stress is an important source of genome instability in cancer cells. Impediments to replication fork progression stimulate the accumulation of RPA-coated single-stranded DNA (RPA-ssDNA). RPA-ssDNA then recruits and activates a large number of genome maintenance factors including the master checkpoint kinase ATR to protect genomic integrity. Amongst the factors recruited onto RPA-ssDNA, we have previously shown that the E3 ubiquitin ligase PRP19, in addition to its central role as an RNA splicing factor, plays an integral part in the elicitation of the DDR during replication stress. Specifically, the ubiquitin l...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Dubois, J.-C., Clement, G., Cappadocia, L., Gaudreau, L., Zou, L., Marechal, A. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA03: Targeting the DNA damage response to generate new medicines for cancer treatment
Cancers are characterized by high levels of genomic instability and endogenous DNA damage. Traditional cancer therapies include radiotherapy and DNA-damaging chemotherapy, but these treatments are associated with significant damage to normal tissue. These unwanted side effects may be reduced by using targeted treatment approaches that preferentially affect tumor cells with specific mutations. The DNA damage response (DDR) in cancer cells differs in at least three aspects to those of normal cells, namely the loss of one or more DDR pathway or capability, increased levels of replication stress and higher levels of endogenous...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: O'Connor, M. J. Tags: Keynote Presentations: Oral Presentations - Invited Abstracts Source Type: research
Abstract A03: The EMSY threonine 207 phospho-site is required for EMSY-driven suppression of DNA damage repair
Conclusions: EMSY-overexpressing cells show decreased HDR activity, demonstrating EMSY's relevance to the HDR pathway. Our data support the notion that EMSY-driven HDR impairment is BRCA2-interaction-independent and challenges the currently held impression that EMSY overexpression mimics the BRCA2-depleted phenotype via direct interaction. We found a new phospho-site at EMSY T207 and identified PKA as a targeting kinase. Phosphorylation of EMSY at T207, but not S209 phospho-site is necessary for EMSY-driven suppression of HDR. We suggest that an increase in EMSY's T207 phosphorylation in patients bearing EMSY¬-amplifie...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Jelinic, P., Eccles, L., Tseng, J., Cybulska, P., Powell, S. N., Levine, D. Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR02: Small molecules that specifically inhibit the D-loop activity of RAD51
RAD51 plays a central role in homologous recombination (HR), which maintains genome integrity. RAD51 is commonly overexpressed in cancer cells relative to normal tissue and is considered a therapeutic target in oncology. One potential challenge for targeting RAD51 pharmacologically is that it mediates functions in both double-strand DNA break (DSB) repair and stabilization of stalled replication forks.In order to distinguish compound-mediated effects on these RAD51 functions, we developed a novel class of RAD51 inhibitors. In contrast to many previously reported RAD51 inhibitors, we sought to develop compounds that do not ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Budke, B., Lv, W., Tueckmantel, W., Kozikowski, A., Connell, P. Tags: Homologous Recombination Defects: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA02: Defects in DNA repair genes revealed by clinical sequencing of advanced cancer patients
In 2011, we introduced the Mi-Oncoseq program, an IRB-approved protocol to carry out integrative sequencing of advanced cancer patients. It was one of the first comprehensive DNA and RNA sequencing programs offered for cancer patients. The purpose of this program was to determine the utility of genomic sequencing of tumors and germline coupled with a multi-disciplinary Precision Medicine Tumor Board (PMTB) in the management of advanced cancer patients. Collectively across all patient cohorts we have enrolled over 1500 patients since inception of Mi-Oncoseq where molecular results for both somatic and germline aberrations a...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Chinnaiyan, A. Tags: Keynote Presentations: Oral Presentations - Invited Abstracts Source Type: research
Abstract B02: DNA repair landscape in High Grade Ovarian Cancer (HGOC) and evolution with neo-adjuvant chemotherapy
Conclusions: We present the first study of change in DNA repair protein expression with NACT. At diagnosis, HGOC is associated with loss of key DNA repair proteins in a significant proportion of patients and NACT can induce significant loss of DNA repair proteins. Combined loss of DNA repair proteins was significantly predictive of survival. Work in ongoing to extend this analysis to a greater panel of DNA repair biomarkers.Citation Format: Aurelie Auguste, Soizick Mesnage, Audrey Le Formal, Elena Cojocaru, Francoise Drusch, Julien Adam, Sebastien Gouy, Enrica Bentivegna, Catherine Lhomme, Patricia Pautier, Catherine Genes...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Auguste, A., Mesnage, S., Formal, A. L., Cojocaru, E., Drusch, F., Adam, J., Gouy, S., Bentivegna, E., Lhomme, C., Pautier, P., Genestie, C., Leary, A. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR01: Mechanisms of regulation of the tumor suppressor PALB2
One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9 fold. PALB2 was identified BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. Inherited mutations in PALB2 are associated with a predisposition for ovarian, breast and pancreatic cancers. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination.Therefore, the regulation...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Couturier, A., Buisson, R., Pauty, J., Rodrigue, A., Joshi, N., Caron, M.-C., Coulombe, Y., Zou, L., Masson, J.-Y. Tags: DNA Damage Signaling: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA01: Advancing the field of mutational signatures: Mechanisms and clinical applications
Mutational signatures are the imprints of the biological processes that have gone awry in human cells. We previously outlined the methods for identifying and quantifying base substitution mutational signatures present in primary human cancers (http://cancer.sanger.ac.uk/cosmic/signatures). Here, using a highly-curated cohort of 560 whole genome sequenced breast cancers, we extend the understanding of mutational signatures to include six novel rearrangement signatures. Diving into the detail of individual mutational signatures, we reveal intriguing mechanistic insights into the DNA damage and repair processes that mark the ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Nik-Zainal, S. Tags: Keynote Presentations: Oral Presentations - Invited Abstracts Source Type: research
Abstract B01: Histone acetyltransferase 1 contributes to colon cancer initiating cell chemoresistance through DNA damage repair pathways
Despite advances in treatment, Colorectal cancer (CRC) remains a leading cause of cancer related deaths in North America. Most CRCs contain a subset of self-renewing colon cancer-initiating cells (CC-ICs) responsible for tumor initiation and maintenance. CC-ICs are relatively chemoresistant as compared to the bulk tumor cells, however the mechanisms of this chemoresistance are poorly understood. An increasing amount of evidence suggests that epigenetic regulators may be playing a central role in driving CC-IC chemoresistance; one such example being histone acetyltransferase (HAT1), which plays an important role in cancer c...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Agro, L., Leung, C., Wang, Y., Lima-Fernandes, E., O'Brien, C. Tags: DNA Damage Signaling: Poster Presentations - Proffered Abstracts Source Type: research
IGF-1 Receptor Modulates FoxO1-Mediated Tamoxifen Response in Breast Cancer Cells
Tamoxifen is a common adjuvant treatment for estrogen receptor (ER)α-positive patients with breast cancer; however, acquired resistance abrogates the efficacy of this therapeutic approach. We recently demonstrated that G protein–coupled estrogen receptor 1 (GPER1) mediates tamoxifen action in breast cancer cells by inducing insulin-like growth factor–binding protein-1 (IGFBP-1) to inhibit IGF-1–dependent signaling. To determine whether dysregulation of IGFBP-1 induction is associated with tamoxifen resistance, IGFBP-1 transcription was measured in tamoxifen-resistant MCF-7 cells (TamR) after tamoxif...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Vaziri-Gohar, A., Zheng, Y., Houston, K. D. Tags: Signal Transduction Source Type: research
Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes. Furthermore, the generation of cells that ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Smigiel, J. M., Parameswaran, N., Jackson, M. W. Tags: Signal Transduction Source Type: research
Inflammatory Molecule, PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NF{kappa}B Signaling
P-selectin glycoprotein ligand 1 (SELPLG/PSGL-1) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. ApcMin/+ mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a ApcMin/+;PSGL-1–/– genotype. The incidence and pathologic features of the intestinal tumors w...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Li, J., Zhou, Z., Zhang, X., Zheng, L., He, D., Ye, Y., Zhang, Q.-Q., Qi, C.-L., He, X.-D., Yu, C., Shao, C.-k., Qiao, L., Wang, L. Tags: Oncogenes and Tumor Suppressors Source Type: research
Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance
This study suggests that the LXN pathway should be further explored as a viable target for preventing or reversing taxane resistance in prostate cancer. Mol Cancer Res; 15(4); 457–66. ©2017 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Zhang, M., Osisami, M., Dai, J., Keller, J. M., Escara-Wilke, J., Mizokami, A., Keller, E. T. Tags: Oncogenes and Tumor Suppressors Source Type: research
miR-211-5p Suppresses Metastatic Behavior by Targeting SNAI1 in Renal Cancer
The Snail family transcriptional repressor 1 (SNAI1) is known to promote metastatic phenotypes in renal cell carcinoma (RCC). However, the mechanism by which SNAI1 promotes RCC metastasis remains largely unexplored. Here, bioinformatics and quantitative validation revealed that miR-211-5p was downregulated in metastatic RCC clinical specimens compared with nonmetastatic RCC tissues. Overexpression of miR-211-5p suppressed RCC cell migration and invasion via downregulation of SNAI1 expression. Luciferase reporter assays demonstrated that miR-211-5p directly targeted 3'-UTR of SNAI1. Furthermore, miR-211-5p decreased xenogra...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Wang, K., Jin, W., Jin, P., Fei, X., Wang, X., Chen, X. Tags: Oncogenes and Tumor Suppressors Source Type: research
Metabolic Profiling in Formalin-Fixed and Paraffin-Embedded Prostate Cancer Tissues
Metabolite profiling has significantly contributed to a deeper understanding of the biochemical metabolic networks and pathways in cancer cells. Metabolomics-based biomarker discovery would greatly benefit from the ability to interrogate retrospective annotated clinical specimens archived as formalin-fixed, paraffin-embedded (FFPE) material. Mass spectrometry–based metabolomic analysis was performed in matched frozen and FFPE human prostate cancers as well as isogenic prostate cancer cell lines. A total of 352 and 460 metabolites were profiled in human tissues and cell lines, respectively. Classes and physical–...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Cacciatore, S., Zadra, G., Bango, C., Penney, K. L., Tyekucheva, S., Yanes, O., Loda, M. Tags: Metabolism Source Type: research
