CUL4A contributes to the biology of basal-like breast tumors through modulation of cell growth and antitumor immune response

The CUL4A E3 ubiquitin ligase is involved in the regulation of many cellular processes and its amplification and/or overexpression has been observed in breast cancer. The 13q34 amplification, which is associated with the basal-like breast cancer subtype, has been proposed as one of the mechanism behind CUL4A up-regulation. However, the specific contribution of CUL4A to the biology of basal-like breast tumors has not yet been elucidated. In this work, by using cellular models of basal phenotype, we show the inhibitory effect of CUL4A silencing in the proliferation and growth of breast cancer cells both, in vitro and in vivo. We also demonstrate the transforming capacity of CUL4A exogenous overexpression in the 184B5 human mammary epithelial cells in vitro. Our results suggest a synergistic effect between CUL4A high levels and the activation of the RAS pathway in the tumorigenesis of basal-like breast cancer tumors. In addition, by using a proteomics approach we have defined novel candidate proteins and pathways that might mediate the oncogenic effect of CUL4A. In particular, we report a putative role of CUL4A in bypassing the immune system in breast cancer through the down-regulation of several molecules involved in the immune surveillance. These findings provide insight into the oncogenic properties of CUL4A in basal-like breast cancer and highlight the therapeutic opportunities to target CUL4A.

[1]  J. Gray,et al.  CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. , 2014, Cancer research.

[2]  Leslie Cope,et al.  HMGA1: A Master Regulator of Tumor Progression in Triple-Negative Breast Cancer Cells , 2013, PloS one.

[3]  C. Brayton,et al.  Knockdown of HMGA1 inhibits human breast cancer cell growth and metastasis in immunodeficient mice. , 2013, Biochemical and biophysical research communications.

[4]  J. Benítez,et al.  Analysis of DNA Repair–Related Genes in Breast Cancer Reveals CUL4A Ubiquitin Ligase as a Novel Biomarker of Trabectedin Response , 2013, Molecular Cancer Therapeutics.

[5]  Anushya Muruganujan,et al.  PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees , 2012, Nucleic Acids Res..

[6]  A. Vincent-Salomon,et al.  Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. , 2012, Cancer research.

[7]  G. Mills,et al.  Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer , 2012, Breast Cancer Research.

[8]  P. L. Bergsagel,et al.  MYC addiction: a potential therapeutic target in MM. , 2012, Blood.

[9]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[10]  S. Fulda,et al.  Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications , 2012, EMBO molecular medicine.

[11]  C. Morrison,et al.  Targeting FACT Complex Suppresses Mammary Tumorigenesis in Her2/neu Transgenic Mice , 2012, Cancer Prevention Research.

[12]  C. Horbinski,et al.  Expression of antigen processing and presenting molecules in brain metastasis of breast cancer , 2012, Cancer Immunology, Immunotherapy.

[13]  Jianni Qi,et al.  Smurf1 Protein Negatively Regulates Interferon-γ Signaling through Promoting STAT1 Protein Ubiquitination and Degradation* , 2012, The Journal of Biological Chemistry.

[14]  Yongwei Yu,et al.  Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer , 2012, Journal of Molecular Medicine.

[15]  L. Carey.  Breast cancer: HER2—a good addiction , 2012, Nature Reviews Clinical Oncology.

[16]  Pengbo Zhou,et al.  Pathogenic Role of the CRL4 Ubiquitin Ligase in Human Disease , 2012, Front. Oncol..

[17]  Simone Fulda,et al.  Targeting IAP proteins for therapeutic intervention in cancer , 2012, Nature Reviews Drug Discovery.

[18]  H. Ngan,et al.  Tumour Suppressive Function and Modulation of Programmed Cell Death 4 (PDCD4) in Ovarian Cancer , 2012, PloS one.

[19]  T. Iftner,et al.  High-Risk Human Papillomaviruses Repress Constitutive Kappa Interferon Transcription via E6 To Prevent Pathogen Recognition Receptor and Antiviral-Gene Expression , 2011, Journal of Virology.

[20]  A. Komar,et al.  Curaxins: Anticancer Compounds That Simultaneously Suppress NF-κB and Activate p53 by Targeting FACT , 2011, Science Translational Medicine.

[21]  J. Mackey,et al.  Association of FABP5 expression with poor survival in triple-negative breast cancer: implication for retinoic acid therapy. , 2011, The American journal of pathology.

[22]  Zicai Liang,et al.  Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein , 2010, Oncogene.

[23]  H. Shih,et al.  The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses , 2010, The EMBO journal.

[24]  Hugo M. Horlings,et al.  Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets , 2009, Oncogene.

[25]  Javier Benítez,et al.  Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes , 2009, Breast Cancer Research.

[26]  A. Camargo,et al.  Epigenetic silencing of CRABP2 and MX1 in head and neck tumors. , 2009, Neoplasia.

[27]  J. Mao,et al.  Cul4A is an oncogene in malignant pleural mesothelioma , 2009, Journal of cellular and molecular medicine.

[28]  Wei Zhou,et al.  In vivo Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast Cancer Models , 2009, Clinical Cancer Research.

[29]  John D. Minna,et al.  Molecular Profiling of Breast Cancer Cell Lines Defines Relevant Tumor Models and Provides a Resource for Cancer Gene Discovery , 2009, PloS one.

[30]  Albert Koong,et al.  Impaired interferon signaling is a common immune defect in human cancer , 2009, Proceedings of the National Academy of Sciences.

[31]  W. Linehan,et al.  Inhibition of Tumor Cell Motility by the Interferon-inducible GTPase MxA* , 2009, Journal of Biological Chemistry.

[32]  K. Sugasawa.  The CUL4 enigma: culling DNA repair factors. , 2009, Molecular cell.

[33]  A. Koff,et al.  CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis. , 2009, Molecular cell.

[34]  M. Loh,et al.  Novel breast cancer metastasis-associated proteins. , 2009, Journal of proteome research.

[35]  A. Ashworth,et al.  A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines , 2009, Breast Cancer Research and Treatment.

[36]  Wenbo Yu,et al.  The phosphorylation of SEPT2 on Ser218 by casein kinase 2 is important to hepatoma carcinoma cell proliferation , 2009, Molecular and Cellular Biochemistry.

[37]  Debra L Winkeljohn.  Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[38]  H. Nishitani,et al.  CDK Inhibitor p21 Is Degraded by a Proliferating Cell Nuclear Antigen-coupled Cul4-DDB1Cdt2 Pathway during S Phase and after UV Irradiation* , 2008, Journal of Biological Chemistry.

[39]  E. Gamelin,et al.  Improved proteome coverage by using iTRAQ labelling and peptide OFFGEL fractionation , 2008, Proteome Science.

[40]  J. Benítez,et al.  Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes , 2008, Oncogene.

[41]  M. Loh,et al.  Differential Expression of Novel Tyrosine Kinase Substrates during Breast Cancer Development *S , 2007, Molecular & Cellular Proteomics.

[42]  F. Kittrell,et al.  Identification of novel amplification gene targets in mouse and human breast cancer at a syntenic cluster mapping to mouse ch8A1 and human ch13q34. , 2007, Cancer research.

[43]  M. Schindl,et al.  Overexpression of the human homologue for Caenorhabditis elegans cul-4 gene is associated with poor outcome in node-negative breast cancer. , 2007, Anticancer research.

[44]  G. Mortier,et al.  qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data , 2007, Genome Biology.

[45]  Trong Khoa Pham,et al.  Technical, experimental, and biological variations in isobaric tags for relative and absolute quantitation (iTRAQ). , 2007, Journal of proteome research.

[46]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[47]  C. Chien,et al.  Functional cooperation between FACT and MCM helicase facilitates initiation of chromatin DNA replication , 2006, The EMBO journal.

[48]  M. Mann,et al.  Parts per Million Mass Accuracy on an Orbitrap Mass Spectrometer via Lock Mass Injection into a C-trap*S , 2005, Molecular & Cellular Proteomics.

[49]  A. Levine,et al.  A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans , 2004, Cell.

[50]  P. Raychaudhuri,et al.  Cul4A Physically Associates with MDM2 and Participates in the Proteolysis of p53 , 2004, Cancer Research.

[51]  A. Jayasurya,et al.  Metallothioneins in human tumors and potential roles in carcinogenesis. , 2003, Mutation research.

[52]  S. Fuchs,et al.  SCFHOS ubiquitin ligase mediates the ligand‐induced down‐regulation of the interferon‐α receptor , 2003 .

[53]  M. Mann,et al.  Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. , 2003, Analytical chemistry.

[54]  Charles M. Perou,et al.  A Comparison of Gene Expression Signatures from Breast Tumors and Breast Tissue Derived Cell Lines , 2002, Disease markers.

[55]  Masakazu Ueda,et al.  TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas , 2002, Hepatology.

[56]  D. N. Perkins,et al.  Probability‐based protein identification by searching sequence databases using mass spectrometry data , 1999, Electrophoresis.

[57]  W. Kuo,et al.  The human homologue for the Caenorhabditis elegans cul-4 gene is amplified and overexpressed in primary breast cancers. , 1998, Cancer research.

[58]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[59]  C. Eyers.  Universal sample preparation method for proteome analysis , 2009 .

[60]  A. Hollestelle,et al.  BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. , 2006, Cancer research.

[61]  S. Fuchs,et al.  SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-alpha receptor. , 2003, The EMBO journal.