Identification of Novel Breast Cancer Risk Loci
It has been estimated that>1,000 genetic loci have yet to be identified for breast cancer risk. Here we report the first study utilizing targeted next-generation sequencing to identify single-nucleotide polymorphisms (SNP) associated with breast cancer risk. Targeted sequencing of 283 genes was performed in 240 women with early-onset breast cancer (≤40 years) or a family history of breast and/or ovarian cancer. Common coding variants with minor allele frequencies (MAF)>1% that were identified were presumed initially to be SNPs, but further database inspections revealed variants had MAF of ≤1% in the general population....
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Claire Hian Tzer Chan, Prabhakaran Munusamy, Sau Yeen Loke, Geok Ling Koh, Edward Sern Yuen Wong, Hai Yang Law, Chui Sheun Yoon, Min-Han Tan, Yoon Sim Yap, Peter Ang, Ann Siew Gek Lee Tags: Prevention and Epidemiology Source Type: research
Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing
Noninvasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers. The tumors represented in the patient cohort were mainly gastrointestinal (31.8%), brain (22.7%), or lung (20.7%). ctDNA obtained from most patients [N = 423 (63%)] displayed at least one alteration. The most frequent alterations seen, as characterized mutations or variants of unknown ...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Maria Schwaederle, Ranajoy Chattopadhyay, Shumei Kato, Paul T. Fanta, Kimberly C. Banks, In Sil Choi, David E. Piccioni, Sadakatsu Ikeda, AmirAli Talasaz, Richard B. Lanman, Lyudmila Bazhenova, Razelle Kurzrock Tags: Clinical Studies Source Type: research
Integrating Models to Quantify Environment-Mediated Drug Resistance
Drug resistance is the single most important driver of cancer treatment failure for modern targeted therapies, and the dialog between tumor and stroma has been shown to modulate the response to molecularly targeted therapies through proliferative and survival signaling. In this work, we investigate interactions between a growing tumor and its surrounding stroma and their role in facilitating the emergence of drug resistance. We used mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating intrinsic and extrinsic components of resistance in BRAF-mutated me...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Noemi Picco, Erik Sahai, Philip K. Maini, Alexander R.A. Anderson Tags: Integrated Systems and Technologies Source Type: research
Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors
Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanis...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Jennifer M. Sahni, Sylvia S. Gayle, Bryan M. Webb, Kristen L. Weber-Bonk, Darcie D. Seachrist, Salendra Singh, Steven T. Sizemore, Nicole A. Restrepo, Gurkan Bebek, Peter C. Scacheri, Vinay Varadan, Matthew K. Summers, Ruth A. Keri Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Combination Therapy with Bispecific Antibodies and PD-1 Blockade Enhances the Antitumor Potency of T Cells
The DOCK-AND-LOCK (DNL) method is a platform technology that combines recombinant engineering and site-specific conjugation to create multispecific, multivalent antibodies of defined composition with retained bioactivity. We have applied DNL to generate a novel class of trivalent bispecific antibodies (bsAb), each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different antitumor Fabs. Here, we report the further characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2– and CEACAM5-expressing cancer cells, respectively. (E1)-3s and (14)-3s, in the ...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Chien-Hsing Chang, Yang Wang, Rongxiu Li, Diane L. Rossi, Donglin Liu, Edmund A. Rossi, Thomas M. Cardillo, David M. Goldenberg Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells
Early-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytome...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Victor A. Gall, Anne V. Philips, Na Qiao, Karen Clise-Dwyer, Alexander A. Perakis, Mao Zhang, Guy T. Clifton, Pariya Sukhumalchandra, Qing Ma, Sangeetha M. Reddy, Dihua Yu, Jeffrey J. Molldrem, George E. Peoples, Gheath Alatrash, Elizabeth A. Mittendorf Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
S100A4 Is a Biomarker and Regulator of Glioma Stem Cells That Is Critical for Mesenchymal Transition in Glioblastoma
Glioma stem cells (GSC) and epithelial–mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here, we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and pat...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Kin-Hoe Chow, Hee Jung Park, Joshy George, Keiko Yamamoto, Andrew D. Gallup, Joel H. Graber, Yuanxin Chen, Wen Jiang, Dennis A. Steindler, Eric G. Neilson, Betty Y.S. Kim, Kyuson Yun Tags: Tumor and Stem Cell Biology Source Type: research
Oncogenic KRAS and p53 Loss Drive Gastric Tumorigenesis in Mice That Can Be Attenuated by E-Cadherin Expression
Gastric adenocarcinoma is the third leading cause of cancer-related death worldwide, but no models exist to readily investigate distant metastases that are mainly responsible for mortality in this disease. Here we report the development of a genetically engineered mouse model of gastric adenocarcinoma tumorigenesis based on KrasG12D expression plus inactivation of E-cadherin (Cdh1) and p53 in the gastric parietal cell lineage. Intestinal and diffuse gastric tumors arise rapidly in this model that displays a median survival of 76 days. Tumors occur throughout the stomach, with metastases documented in lymph nodes, lung, and...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Jacob E. Till, Changhwan Yoon, Bang-Jin Kim, Kerry Roby, Prince Addai, Evan Jonokuchi, Laura H. Tang, Sam S. Yoon, Sandra Ryeom Tags: Tumor and Stem Cell Biology Source Type: research
Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence
Distinguishing between indolent and aggressive prostate adenocarcinoma remains a priority to accurately identify patients who need therapeutic intervention. SIN3B has been implicated in the initiation of senescence in vitro. Here we show that in a mouse model of prostate cancer, SIN3B provides a barrier to malignant progression. SIN3B was required for PTEN-induced cellular senescence and prevented progression to invasive prostate adenocarcinoma. Furthermore, SIN3B was downregulated in human prostate adenocarcinoma correlating with upregulation of its target genes. Our results suggest a tumor suppressor function for SIN3B t...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Anthony J. Bainor, Fang-Ming Deng, Yu Wang, Peng Lee, David J. Cantor, Susan K. Logan, Gregory David Tags: Tumor and Stem Cell Biology Source Type: research
MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress
Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These preneoplastic B lymphocytes did not progress to detec...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Elizabeth Spehalski, Kayla M. Capper, Cheryl J. Smith, Mary J. Morgan, Maria Dinkelmann, Jeffrey Buis, JoAnn M. Sekiguchi, David O. Ferguson Tags: Molecular and Cellular Pathobiology Source Type: research
HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas
Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BU...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Mianen Sun, Pan Tong, Wen Kong, Baijun Dong, Yiran Huang, In Young Park, Lijun Zhou, Xian-De Liu, Zhiyong Ding, Xuesong Zhang, Shanshan Bai, Peter German, Reid Powell, Quan Wang, Xuefei Tong, Nizar M. Tannir, Surena F. Matin, W. Kimryn Rathmell, Gregory N Tags: Molecular and Cellular Pathobiology Source Type: research
Nuclear FAK and Runx1 Cooperate to Regulate IGFBP3, Cell-Cycle Progression, and Tumor Growth
Nuclear focal adhesion kinase (FAK) is a potentially important regulator of gene expression in cancer, impacting both cellular function and the composition of the surrounding tumor microenvironment. Here, we report in a murine model of skin squamous cell carcinoma (SCC) that nuclear FAK regulates Runx1-dependent transcription of insulin-like growth factor binding protein 3 (IGFBP3), and that this regulates SCC cell-cycle progression and tumor growth in vivo. Furthermore, we identified a novel molecular complex between FAK and Runx1 in the nucleus of SCC cells and showed that FAK interacted with a number of Runx1-regulatory...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Marta Canel, Adam Byron, Andrew H. Sims, Jessy Cartier, Hitesh Patel, Margaret C. Frame, Valerie G. Brunton, Bryan Serrels, Alan Serrels Tags: Molecular and Cellular Pathobiology Source Type: research
JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity
Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Juan Ye, Tian-Sheng Li, Gang Xu, Yi-Ming Zhao, Ning-Ping Zhang, Jia Fan, Jian Wu Tags: Molecular and Cellular Pathobiology Source Type: research
Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis
Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide, wh...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Yun-Chi Tang, Hui Yuwen, Kaiying Wang, Peter M. Bruno, Kevin Bullock, Amy Deik, Stefano Santaguida, Marianna Trakala, Sarah J. Pfau, Na Zhong, Tao Huang, Lan Wang, Clary B. Clish, Michael T. Hemann, Angelika Amon Tags: Molecular and Cellular Pathobiology Source Type: research
PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma
In this study, we report the establishment of a spheroid culture method that enriches early-stage tumor cells from TH-MYCN mice, a preclinical model of neuroblastoma. Using this method, we found that tumorigenic cells were evident as early as day E13.5 during embryo development, when the MYC and PRC2 transcriptomes were significantly altered. Ezh2, an essential component of PRC2, was expressed in embryonic and postnatal tumor lesions and physically associated with N-MYC and we observed that H3K27me3 was increased at PRC2 target genes. PRC2 inhibition suppressed in vitro sphere formation, derepressed its target genes, and s...
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Authors: Shoma Tsubota, Satoshi Kishida, Teppei Shimamura, Miki Ohira, Satoshi Yamashita, Dongliang Cao, Shinichi Kiyonari, Toshikazu Ushijima, Kenji Kadomatsu Tags: Molecular and Cellular Pathobiology Source Type: research
