Qing Sheng

Publications (10)183.72 Total impact

• Article: An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells.

  Qing Sheng, Xinggang Liu, Eleanor Fleming, Karen Yuan, Huiying Piao, Jinyun Chen, Zeinab Moustafa, Roman K Thomas, Heidi Greulich, Anna Schinzel, Sara Zaghlul, David Batt, Seth Ettenberg, Matthew Meyerson, Birgit Schoeberl, Andrew L Kung, William C Hahn, Ronny Drapkin, David M Livingston, Joyce F Liu
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  ABSTRACT: Ovarian cancer is a leading cause of death from gynecologic malignancies. Treatment for advanced-stage disease remains limited and, to date, targeted therapies have been incompletely explored. By systematically suppressing each human tyrosine kinase in ovarian cancer cell lines by RNAi, we found that an autocrine signal-transducing loop involving NRG1 and activated ErbB3 operates in a subset of primary ovarian cancers and ovarian cancer cell lines. Perturbation of this circuit with ErbB3-directed RNAi decreased cell growth in three-dimensional culture and resulted in decreased disease progression and prolonged survival in a xenograft mouse model of ovarian cancer. Furthermore, a monoclonal ErbB3-directed antibody (MM-121) also significantly inhibited tumor growth in vivo. These findings identify ErbB3 as a potential therapeutic target in ovarian cancer.
  Cancer cell 03/2010; 17(3):298-310. · 25.29 Impact Factor
• Article: Overexpression of elafin in ovarian carcinoma is driven by genomic gains and activation of the nuclear factor kappaB pathway and is associated with poor overall survival.

  Adam Clauss, Vivian Ng, Joyce Liu, Huiying Piao, Moises Russo, Natalie Vena, Qing Sheng, Michelle S Hirsch, Tomas Bonome, Ursula Matulonis, Azra H Ligon, Michael J Birrer, Ronny Drapkin
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  ABSTRACT: Ovarian cancer is a leading cause of cancer mortality in women. The aim of this study was to elucidate whether whey acidic protein (WAP) genes on chromosome 20q13.12, a region frequently amplified in this cancer, are expressed in serous carcinoma, the most common form of the disease. Herein, we report that a trio of WAP genes (HE4, SLPI, and Elafin) is overexpressed and secreted by serous ovarian carcinomas. To our knowledge, this is the first report linking Elafin to ovarian cancer. Fluorescence in situ hybridization analysis of primary tumors demonstrates genomic gains of the Elafin locus in a majority of cases. In addition, a combination of peptidomimetics, RNA interference, and chromatin immunoprecipitation experiments shows that Elafin expression can be transcriptionally upregulated by inflammatory cytokines through activation of the nuclear factor kappaB pathway. Importantly, using a clinically annotated tissue microarray composed of late-stage, high-grade serous ovarian carcinomas, we show that Elafin expression correlates with poor overall survival. These results, combined with our observation that Elafin is secreted by ovarian tumors and is minimally expressed in normal tissues, suggest that Elafin may serve as a determinant of poor survival in this disease.
  Neoplasia (New York, N.Y.) 02/2010; 12(2):161-72. · 5.48 Impact Factor
• Source

  Available from: Susan E Moody

  Article: Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.

  David A Barbie, Pablo Tamayo, Jesse S Boehm, So Young Kim, Susan E Moody, Ian F Dunn, Anna C Schinzel, Peter Sandy, Etienne Meylan, Claudia Scholl, [......], David M Livingston, David M Sabatini, Matthew Meyerson, Roman K Thomas, Eric S Lander, Jill P Mesirov, David E Root, D Gary Gilliland, Tyler Jacks, William C Hahn
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  ABSTRACT: The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
  Nature 11/2009; 462(7269):108-12. · 36.28 Impact Factor
• Article: AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

  Krishna M Vasudevan, David A Barbie, Michael A Davies, Rosalia Rabinovsky, Chontelle J McNear, Jessica J Kim, Bryan T Hennessy, Hsiuyi Tseng, Panisa Pochanard, So Young Kim, [......], Ana Maria Gonzalez-Angulo, Ana Lluch, Lucia E Rameh, Tyler Jacks, David E Root, Eric S Lander, Gordon B Mills, William C Hahn, William R Sellers, Levi A Garraway
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  ABSTRACT: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.
  Cancer cell 08/2009; 16(1):21-32. · 25.29 Impact Factor
• Source

  Available from: Johanna Schleutker

  Article: A recurrent mutation in PALB2 in Finnish cancer families.

  Hannele Erkko, Bing Xia, Jenni Nikkilä, Johanna Schleutker, Kirsi Syrjäkoski, Arto Mannermaa, Anne Kallioniemi, Katri Pylkäs, Sanna-Maria Karppinen, Katrin Rapakko, [......], Arja Jukkola-Vuorinen, Aki Mustonen, Juha Kere, Lauri A Aaltonen, Veli-Matti Kosma, Vesa Kataja, Ylermi Soini, Ronny I Drapkin, David M Livingston, Robert Winqvist
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  ABSTRACT: BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.
  Nature 04/2007; 446(7133):316-9. · 36.28 Impact Factor
• Article: Fanconi anemia is associated with a defect in the BRCA2 partner PALB2.

  Bing Xia, Josephine C Dorsman, Najim Ameziane, Yne de Vries, Martin A Rooimans, Qing Sheng, Gerard Pals, Abdellatif Errami, Eliane Gluckman, Julian Llera, Weidong Wang, David M Livingston, Hans Joenje, Johan P de Winter
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  ABSTRACT: The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion.
  Nature Genetics 03/2007; 39(2):159-61. · 35.53 Impact Factor
• Article: Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.

  Bing Xia, Qing Sheng, Koji Nakanishi, Akihiro Ohashi, Jianmin Wu, Nicole Christ, Xinggang Liu, Maria Jasin, Fergus J Couch, David M Livingston
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  ABSTRACT: BRCA2 mutations predispose carriers to breast and ovarian cancer and can also cause other cancers and Fanconi anemia. BRCA2 acts as a "caretaker" of genome integrity by enabling homologous recombination (HR)-based, error-free DNA double-strand break repair (DSBR) and intra-S phase DNA damage checkpoint control. Described here is the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function.
  Molecular Cell 07/2006; 22(6):719-29. · 14.18 Impact Factor
• Article: Activation of CREB/ATF sites by polyomavirus large T antigen.

  Tara M Love, Rowena de Jesus, Jennifer A Kean, Qing Sheng, Andrew Leger, Brian Schaffhausen
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  ABSTRACT: Polyomavirus large T antigen (LT) has a direct role in viral replication and a profound effect on cell phenotype. It promotes cell cycle progression, immortalizes primary cells, blocks differentiation, and causes apoptosis. While much of large T function is related to its effects on tumor suppressors of the retinoblastoma susceptibility (Rb) gene family, we have previously shown that activation of the cyclin A promoter can occur through a non-Rb-dependent mechanism. Here we show that activation occurs via an ATF/CREB site. Investigation of the mechanism indicates that large T can synergize with CREB family members to activate transcription. Experiments with Gal4-CREB constructs show that synergy is independent of CREB phosphorylation by protein kinase A. Examination of synergy with Gal4-CREB deletion constructs indicates that large T acts on the constitutive activation domain of CREB. Large T can bind to CREB in vivo. Genetic analysis shows that the DNA-binding domain (residues 264 to 420) is sufficient to activate transcription when it is localized to the nucleus. Further analysis of the DNA-binding domain shows that while site-specific DNA binding is not required, non-site-specific DNA binding is important for the activation. Thus, CREB binding and DNA binding are both important for large T activation of CREB/ATF sites. In contrast to previous models where large T transactivation occurred indirectly, these results also suggest that large T can act directly at promoters to activate transcription.
  Journal of Virology 05/2005; 79(7):4180-90. · 5.40 Impact Factor
• Article: Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1

  David A Barbie, Pablo Tamayo, Jesse S Boehm, So Young Kim, Susan E Moody, Ian F Dunn, Anna C Schinzel, Peter Sandy, Etienne Meylan, Claudia Scholl, [......], David M Livingston, David M Sabatini, Matthew Meyerson, Roman K Thomas, Eric S Lander, Jill P Mesirov, David E Root, D Gary Gilliland, Tyler Jacks, William C Hahn
  Nature, v.462, 108-112 (2009).
• Article: An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells

  Qing Sheng, Xinggang Liu, Eleanor Fleming, Karen Yuan, Jinyun Chen, Zeinab Moustafa, Roman K Thomas, Heidi Greulich, Anna C Schinzel, Sara Zaghlul, David Batt, Seth Ettenberg, Matthew Meyerson, Birgit Schoeberl, Andrew L Kung, William C Hahn, Ronny Drapkin, David M Livingston, Joyce Liu
  Cancer Cell, v.17, 298-310 (2010).