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The UPS: a promising target for breast cancer treatment

By Ko Sato, Eeson Rajendra and Tomohiko Ohta


During the past decade, progress in endocrine therapy and the use of trastuzumab has significantly contributed to the decline in breast cancer mortality for hormone receptor-positive and ERBB2 (HER2)-positive cases, respectively. As a result of these advances, a breast cancer cluster with poor prognosis that is negative for the estrogen receptor (ESR1), the progesterone receptor (PRGR) and ERBB2 (triple negative) has come to the forefront of medical therapeutic attention. DNA microarray analyses have revealed that this cluster is phenotypically most like the basal-like breast cancer that is caused by deficiencies in the BRCA1 pathways. To gain further improvements in breast cancer survival, new types of drugs might be required, and small molecules targeting the ubiquitin proteasome system have moved into the spotlight. The success of bortezomib in the treatment of multiple myeloma has sent encouraging signals that proteasome inhibitors could be used to treat other types of cancers. In addition, ubiquitin E3s involved in ESR1, ERBB2 or BRCA1 pathways could be ideal targets for therapeutic intervention. This review summarizes the ubiquitin proteasome pathways related to these proteins and discusses the possibility of new drugs for the treatment of breast cancers

Topics: Review
Publisher: BioMed Central
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Provided by: PubMed Central

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  1. (2006). A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling.
  2. (2005). A genomic and functional inventory of deubiquitinating enzymes. Cell
  3. (2007). A: A mouse model of basal-like breast carcinoma with metaplastic elements.
  4. (2006). AE: Genetic and expression aberrations of E3 ubiquitin ligases in human breast cancer. Mol Cancer Res
  5. (2003). Akslen LA: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer.
  6. (2004). Ashworth A: Hallmarks of BRCAness in sporadic cancers. Nat Rev Cancer
  7. (2006). ATM and breast cancer susceptibility. Oncogene
  8. (2004). Back to the future with ubiquitin. Cell
  9. (2003). Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Proc Natl Acad Sci USA
  10. (2006). Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner. Mol Cancer Ther
  11. (2006). Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol
  12. (2006). BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev
  13. (2007). Bruserud O: The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells.
  14. (2001). C: The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol
  15. (2004). Cancer Case-Control Consortium: CHEK2*1100 delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies.
  16. (2005). Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet
  17. (2001). Cancerpredisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA
  18. (2008). Characterization of a novel cell line establishedBMC Biochemistry
  19. (2005). Chiba N: BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II.
  20. (1998). Ciechanover A: The ubiquitin system. Annu Rev Biochem
  21. (2004). Coactivator AIB1 links estrogen receptor transcriptional activity and stability.
  22. (1999). Conaway JW: Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science
  23. (1999). Crews CM: Eponemycin exerts its antitumor effect through the inhibition of proteasome function. Cancer Res
  24. (1999). Crews CM: Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci USA
  25. (1999). Crews CM: Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology. Bioorg Med Chem Lett
  26. (2006). DB: E6AP and calmodulin reciprocally regulate estrogen receptor stability.
  27. (1997). DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med
  28. (2007). Degradation of HER2 by Cbl-based chimeric ubiquitin ligases. Cancer Res
  29. (2000). Deurs B: Rab7: a key to lysosome biogenesis. Mol Biol Cell
  30. (1998). Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers.
  31. (2002). Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes.
  32. (2006). DM: Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev
  33. (2001). DP: The human estrogen receptoralpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.
  34. (2002). Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy.
  35. (1986). DT: The incidence and gene frequency of ataxia-telangiectasia in the United States.
  36. (2004). E: BRCA1: BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet
  37. (2006). E: Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility. Hum Mol Genet
  38. (2004). Eddins MJ: Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta
  39. (2005). EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol
  40. (2007). EGFR gene and protein expression in breast cancers.
  41. (1992). Epoxomicin, a new antitumor agent of microbial origin.
  42. (2003). ErbB2 degradation mediated by the co-chaperone protein CHIP.
  43. (2007). Estrogen receptor alpha is a putative substrate for the BRCA1 ubiquitin ligase. Proc Natl Acad Sci USA
  44. (2007). et al.: BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene
  45. (2006). EY: Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science
  46. (2003). F: Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell
  47. (2003). Fenical W: Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl
  48. (2006). Ganesan S: X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell
  49. (2003). Giordano S: Negative receptor signalling.
  50. (2003). Haplo-insufficiency of BRCA1 in sporadic breast cancer. Cancer Res
  51. (2007). Hatakeyama S: Ligand-dependent transcription of estrogen receptor alpha is mediated by the ubiquitin ligase EFP. Biochem Biophys Res Commun
  52. (2004). High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell
  53. (2002). Hiom K: Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains.
  54. (2000). Hortobagyi GN: Ongoing and planned adjuvant trials with trastuzumab. Semin Oncol
  55. (1996). Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet
  56. (2007). JD: A mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin ligase. Proc Natl Acad Sci USA
  57. (2004). JD: BRCA1-dependent ubiquitination of gammatubulin regulates centrosome number. Mol Cell Biol
  58. (2005). JL: BRCA1/BARD1 inhibition of mRNA 3' processing involves targeted degradation of RNA polymerase II. Genes Dev
  59. (1999). JS: Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol
  60. (2005). KC: A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell
  61. (2003). KC: A phase 2 study of bortezomib in relapsed, refractory myeloma.
  62. (2001). KC: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res
  63. (2006). King MC: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.
  64. (2005). KP: CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycininduced degradation of estrogen receptor-alpha. Mol Endocrinol
  65. (2004). Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor.
  66. (2004). Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase.
  67. (2000). Molecular portraits of human breast tumours. Nature
  68. (2002). MR: CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100 delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet
  69. (1997). NE: ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling.
  70. (2000). NE: The ErbB signaling network: receptor heterodimerization in development and cancer.
  71. (2002). Neckers L: Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci USA
  72. (1999). O'Malley BW: Proteasome-dependent degradation of the human estrogen receptor.
  73. (2000). O'Malley BW: The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. Mol Cell
  74. (1999). O'Malley BW: The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol Cell Biol
  75. (2007). Ohta T: BRCA1 ubiquitinates RPB8 in response to DNA damage. Cancer Res
  76. (2004). Ohta T: Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase.
  77. (1990). Oki T: Eponemycin, a new antibiotic active against
  78. (2002). Pan ZQ: Autoubiquitination of the BRCA1-BARD1 RING ubiquitin ligase.
  79. (2006). Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations. Oncogene
  80. (2003). Peroxisome proliferator-activated receptor gamma agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor alpha in MCF-7 breast cancer cells. Cancer Res
  81. (2005). Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res
  82. (2006). Proteasome inhibitor drugs on the rise. Cancer Res
  83. (2006). Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res
  84. (2003). Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA
  85. (2007). Riezman H: Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science
  86. (2007). RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell
  87. (2001). S: MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells. Biochem Biophys Res Commun
  88. (2003). S: The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Mol Cell Biol
  89. (2006). Shang Y: The catalytic subunit of the proteasome is engaged in the entire process of estrogen receptor-regulated transcription.
  90. (1997). Simpfendorfer D: Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res
  91. (2007). Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA
  92. (2001). T: The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation.
  93. (2000). Tanigawa N: Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res
  94. (2006). Targeting the AIB1 oncogene through mammalian target of rapamycin inhibition in the mammary gland. Cancer Res
  95. (2003). The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin.
  96. (2003). The proteasome: structure, function, and role in the cell. Cancer Treat Rev
  97. (2000). Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res
  98. (2004). Ubiquitin and breast cancer. Oncogene
  99. (1999). Xiong Y: ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell
  100. (1998). Yarden Y: c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev
  101. (2003). Yarden Y: Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation.
  102. (2000). Yarden Y: Molecular mechanisms underlying ErbB2/ HER2 action in breast cancer. Oncogene

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