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Antitumor protein therapy; Application of the protein transduction domain to the development of a protein drug for cancer treatment

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Abstract

The genomic information obtained through the human genome project has been accelerating the analysis of the functions of various disease relevant genes. The high molecular weight biomolecules, including oligonucleotides, antisense nucleotides, small interference RNA and peptides, as well as genes (cDNA) and proteins, are becoming increasingly important for the development of molecular therapies. However, the potential of such information-rich macromolecules for therapeutic use has been limited by the poor permeability across the lipid bilayer of the cellular plasma membrane. Over the past decade, a unique activity of oligopeptides, known as protein transduction domains (PTDs) or cell penetrating peptides (CPPs), has made it possible to transduce biologically active macromolecules into living cellsin vitro by conjugating a PTD to the desired macromolecule. Furthermore, this activity has also enabled the systemic delivery of bioactive macromolecules to all tissues in living animals. However, we are now confronted with the next difficulty delivering the macromolecules specifically to the therapeutic targetsin vivo. In this review, we focus on the application of PTD to develop antitumor macromolecules and introduce several representative strategies to discriminate between tumor and normal tissue. In addition, we discuss the unique characteristics of breast cancer, which are expected to facilitate the application of PTD to develop novel protein therapy for breast cancer.

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Abbreviations

PTD:

Protein transduction domain

CPP:

Cell penetrating peptide

HIF:

Hypoxia-inducible factor

TAT:

Transcriptional activator of transcription

HIV-1:

Human immunodeficiency virus-1

IGF-I:

Insulin-like growth factor-I

IGF-IR:

IGF-I receptor

RCC:

Renal cell carcinoma

VHL:

Von Hippel-Lindau

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cell

OVA:

Ovalbumin

TRP2:

Tyrosinase-related protein 2

IAP:

Inhibitors of apoptosis protein

Smac:

Second mitochondria-derived activator of caspases

XIAP:

X-linked IAP

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

ODD:

Oxygen-dependent degradation

β-Gal:

β-galactosidase

TOP3:

TAT-ODD-Procaspase-3

AI:

Apoptosis index

pO2 :

Oxygen partial pressure

RNAP:

RNA polymerase

References

  1. Torchilin VP, Rammohan R, Weissig V, Levchenko TS: TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors.Proc Natl Acad Sci USA 98:8786–8791, 2001.

    Article  PubMed  CAS  Google Scholar 

  2. Yamada T, Iwasaki Y, Tada H, Iwabuki H, Chuah MK, VandenDriessche T, Fukuda H, Kondo A, Ueda M, Seno M, Tanizawa K, Kuroda S: Nanoparticles for the delivery of genes and drugs to human hepatocytes.Nat Biotechnol 21:885–890, 2003.

    Article  PubMed  CAS  Google Scholar 

  3. Qian ZM, Li H, Sun H, Ho K: Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway.Pharmacol Rev 54:561–587, 2002.

    Article  PubMed  CAS  Google Scholar 

  4. Green M, Loewenstein PM: Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein.Cell 55:1179–1188, 1988.

    Article  PubMed  CAS  Google Scholar 

  5. Frankel AD, Pabo CO: Cellular uptake of the tat protein from human immunodeficiency virus.Cell 55:1189–1193, 1988.

    Article  PubMed  CAS  Google Scholar 

  6. Becker-Hapak M, McAllister SS, Dowdy SF: TAT-mediated protein transduction into mammalian cells.Methods 24:247–256, 2001.

    Article  PubMed  CAS  Google Scholar 

  7. Jarver P, Langel U: The use of cell-penetrating peptides as a tool for gene regulation.Drug Discov Today 9:395–402, 2004.

    Article  PubMed  Google Scholar 

  8. Futaki S: Membrane-permeable arginine-rich peptides and the translocation mechanisms.Adv Drug Deliv Rev 57:547–558, 2005.

    Article  PubMed  CAS  Google Scholar 

  9. Fawell S, Seery J, Daikh Y, Moore C, Chen LL, Pepinsky B, Barsoum J: Tat-mediated delivery of heterologous proteins into cells.Proc Natl Acad Sci USA 91:664–668, 1994.

    Article  PubMed  CAS  Google Scholar 

  10. Astriab-Fisher A, Sergueev DS, Fisher M, Shaw BR, Juliano RL: Antisense inhibition of P-glycoprotein expression using peptide-oligonucleotide conjugates.Biochem Pharmacol 60:83–90, 2000.

    Article  PubMed  CAS  Google Scholar 

  11. Lewin M, Carlesso N, Tung CH, Tang XW, Cory D, Scadden DT, Weissleder R: Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.Nat Biotechnol 18:410–414, 2000.

    Article  PubMed  CAS  Google Scholar 

  12. Eguchi A, Akuta T, Okuyama H, Senda T, Yokoi H, Inokuchi H, Fujita S, Hayakawa T, Takeda K, Hase-gawa M, Nakanishi M: Protein transduction domain of HrV-1 Tat protein promotes efficient delivery of DNA into mammalian cells.J Biol Chem 276:26204–26210, 2001.

    Article  PubMed  CAS  Google Scholar 

  13. Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF: Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb.Proc Natl Acad Sci USA 94:10699–10704, 1997.

    Article  PubMed  CAS  Google Scholar 

  14. Troy CM, Stefanis L, Prochiantz A, Greene LA, She-lanski ML: The contrasting roles of ICE family proteases and interleukin-1beta in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation.Proc Natl Acad Sci USA 93:5635–5640, 1996.

    Article  PubMed  CAS  Google Scholar 

  15. Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF: In vivo protein transduction: delivery of a biologically active protein into the mouse.Science 285:1569–1572, 1999.

    Article  PubMed  CAS  Google Scholar 

  16. Harada H, Hiraoka M, Kizaka-Kondoh S: Antitumor effect of TAT-oxygen-dependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells.Cancer Res 62:2013–2018, 2002.

    PubMed  CAS  Google Scholar 

  17. Inoue M, Mukai M, Hamanaka Y, Tatsuta M, Hiraoka M, Kizaka-Kondoh S: Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites.Int J Oncol 25:713–720, 2004.

    PubMed  CAS  Google Scholar 

  18. Harbour JW, Worley L, Ma D, Cohen M: Transducible peptide therapy for uveal melanoma and retinoblastoma.Arch Ophthalmol 120:1341–1346, 2002.

    PubMed  CAS  Google Scholar 

  19. Yang L, Mashima T, Sato S, Mochizuki M, Sakamoto H, Yamori T, Oh-Hara T, Tsuruo T: Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide.Cancer Res 63:831–837, 2003.

    PubMed  CAS  Google Scholar 

  20. Datta K, Sundberg C, Karumanchi SA, Mukhopadhyay D: The 104–123 amino acid sequence of the beta-domain of von Hippel-Lindau gene product is sufficient to inhibit renal tumor growth and invasion.Cancer Res 61:1768–1775, 2001.

    PubMed  CAS  Google Scholar 

  21. Vives E, Brodin P, Lebleu B: A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus.J Biol Chem 272:16010–16017, 1997.

    Article  PubMed  CAS  Google Scholar 

  22. Derossi D, Calvet S, Trembleau A, Brunissen A, Chassaing G, Prochiantz A: Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent.J Biol Chem 271:18188–18193, 1996.

    Article  PubMed  CAS  Google Scholar 

  23. Lundberg M, Wikstrom S, Johansson M: Cell surface adherence and endocytosis of protein transduction domains.Mol Ther 8:143–150, 2003.

    Article  PubMed  CAS  Google Scholar 

  24. Richard JP, Melikov K, Vives E, Ramos C, Verbeure B, Gait MJ, Chernomordik LV, Lebleu B: Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake.J Biol Chem 278:585–590, 2003.

    Article  PubMed  CAS  Google Scholar 

  25. Liu Y, Jones M, Hingtgen CM, Bu G, Laribee N, Tanzi RE, Moir RD, Nath A, He JJ: Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands.Nat Med 6:1380–1387, 2000.

    Article  PubMed  CAS  Google Scholar 

  26. Tyagi M, Rusnati M, Presta M, Giacca M: Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans.J Biol Chem 276:3254–3261, 2001.

    Article  PubMed  CAS  Google Scholar 

  27. Console S, Marty C, Garcia-Echeverria C, Schwen-dener R, Ballmer-Hofer K: Antennapedia and HIV transactivator of transcription (TAT) “protein transduction domains” promote endocytosis of high molecular weight cargo upon binding to cell surface gly-cosaminoglycans.J Biol Chem 278:35109–35114, 2003.

    Article  PubMed  CAS  Google Scholar 

  28. Fittipaldi A, Ferrari A, Zoppe M, Arcangeli C, Pellegrini V, Beltram F, Giacca M: Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 Tat fusion proteins.J Biol Chem 278:34141–34149, 2003.

    Article  PubMed  CAS  Google Scholar 

  29. Wadia JS, Stan RV, Dowdy SF: Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis.Nat Med 10:310–315, 2004.

    Article  PubMed  CAS  Google Scholar 

  30. Richard JP, Melikov K, Brooks H, Prevot P, Lebleu B, Chernomordik LV: Cellular Uptake of Unconjugated TAT Peptide Involves Clathrin-dependent Endocytosis and Heparan Sulfate Receptors.J Biol Chem 280:15300–15306, 2005.

    Article  PubMed  CAS  Google Scholar 

  31. Vousden KH, Lu X: Live or let die: the cell’s response to p53.Nat Rev Cancer 2:594–604, 2002.

    Article  PubMed  CAS  Google Scholar 

  32. Momand J, Zambetti GP, Olson DC, George D, Levine AJ: The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.Cell 69:1237–1245, 1992.

    Article  PubMed  CAS  Google Scholar 

  33. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53.Cell 63:1129–1136, 1990.

    Article  PubMed  CAS  Google Scholar 

  34. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ: Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2.Proc Natl Acad Sci USA 95:8292–8297, 1998.

    Article  PubMed  CAS  Google Scholar 

  35. Vogelstein B, Lane D, Levine AJ: Surfing the p53 network.Nature 408:307–310, 2000.

    Article  PubMed  CAS  Google Scholar 

  36. Sherr CJ, McCormick F: The RB and p53 pathways in cancer.Cancer Cell 2:103–112, 2002.

    Article  PubMed  CAS  Google Scholar 

  37. Roth JA, Nguyen D, Lawrence DD, Kemp BL, Carrasco CH, Ferson DZ, Hong WK, Komaki R, Lee JJ, Nes-bitt JC, Pisters KM, Putnam JB, Schea R, Shin DM, Walsh GL, Dolormente MM, Han CI, Martin FD, Yen N, Xu K, Stephens LC, McDonnell TJ, Mukhopad-hyay T, Cai D: Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.Nat Med 2:985–991, 1996.

    Article  PubMed  CAS  Google Scholar 

  38. Seth P, Katayose D, Li Z, Kim M, Wersto R, Craig C, Shanmugam N, Ohri E, Mudahar B, Rakkar AN, Kodali P, Cowan K: A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers.Cancer Gene Ther 4:383–390, 1997.

    PubMed  CAS  Google Scholar 

  39. McCormick F: Cancer gene therapy: fringe or cutting edge?Nat Rev Cancer 1:130–141, 2001.

    Article  PubMed  CAS  Google Scholar 

  40. Wu X, Bayle JH, Olson D, Levine AJ: The p53-mdm-2 autoregulatory feedback loop.Genes Dev 7:1126–1132, 1993.

    Article  PubMed  CAS  Google Scholar 

  41. Polsky D, Melzer K, Hazan C, Panageas KS, Busam K, Drobnjak M, Kamino H, Spira JG, Kopf AW, Houghton A, Cordon-Cardo C, Osman I: HDM2 protein overexpression and prognosis in primary malignant melanoma.J Natl Cancer Inst 94:1803–1806, 2002.

    PubMed  CAS  Google Scholar 

  42. Mori S, Ito G, Usami N, Yoshioka H, Ueda Y, Kodama Y, Takahashi M, Fong KM, Shimokata K, Sekido Y: p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma.Cancer 100:1673–1682, 2004.

    Article  PubMed  CAS  Google Scholar 

  43. Berger AJ, Camp RL, Divito KA, Kluger HM, Halaban R, Rimm DL: Automated quantitative analysis of HDM2 expression in malignant melanoma shows association with early-stage disease and improved outcome.Cancer Res 64:8767–8772, 2004.

    Article  PubMed  CAS  Google Scholar 

  44. Lowe SW, Lin AW: Apoptosis in cancer.Carcinogenesis 21:485–495, 2000.

    Article  PubMed  CAS  Google Scholar 

  45. Goyal L: Cell death inhibition: keeping caspases in check.Cell 104:805–808, 2001.

    Article  PubMed  CAS  Google Scholar 

  46. Deveraux QL, Reed JC: IAP family proteins-suppressors of apoptosis.Genes Dev 13:239–252, 1999.

    Article  PubMed  CAS  Google Scholar 

  47. Nachmias B, Ashhab Y, Ben-Yehuda D: The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer.Semin Cancer Biol 14:231–243, 2004.

    Article  PubMed  CAS  Google Scholar 

  48. Deveraux QL, Takahashi R, Salvesen GS, Reed JC: X-linked IAP is a direct inhibitor of cell-death proteases.Nature 388:300–304, 1997.

    Article  PubMed  CAS  Google Scholar 

  49. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC: The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases.EMBO J 16:6914–6925, 1997.

    Article  PubMed  CAS  Google Scholar 

  50. Du C, Fang M, Li Y, Li L, Wang X: Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.Cell 102:33–42 2000.

    Article  PubMed  CAS  Google Scholar 

  51. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL: Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.Cell 102:43–53, 2000.

    Article  PubMed  CAS  Google Scholar 

  52. Fulda S, Wick W, Weller M, Debatin KM: Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo.Nat Med 8:808–815, 2002.

    PubMed  CAS  Google Scholar 

  53. Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y: Structural basis of IAP recognition by Smac/DIA-BLO.Nature 408:1008–1012, 2000.

    Article  PubMed  CAS  Google Scholar 

  54. Prager D, Li HL, Asa S, Melmed S: Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor I receptor mutant.Proc Natl Acad Sci USA 91:2181–2185, 1994.

    Article  PubMed  CAS  Google Scholar 

  55. Kalebic T, Tsokos M, Helman LJ: In vivo treatment with antibody against IGF-1 receptor suppresses growth of human rhabdomyosarcoma and down-regulates p34cdc2.Cancer Res 54:5531–5534, 1994.

    PubMed  CAS  Google Scholar 

  56. Lee CT, Wu S, Gabrilovich D, Chen H, Nadaf-Rahrov S, Ciernik IF, Carbone DP: Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines.Cancer Res 56:3038–3041, 1996.

    PubMed  CAS  Google Scholar 

  57. Datta K, Nambudripad R, Pal S, Zhou M, Cohen HT, Mukhopadhyay D: Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer.J Biol Chem 275:20700–20706, 2000.

    Article  PubMed  CAS  Google Scholar 

  58. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, Lubensky I, Duan DR, Florence C, Pzzatti R, Walther MM, Bander NH, Grossman HB, Brauch H, Pomer S, Brooks JD, Isaacs WB, Lerman MI, Zbar B, Linehan WM: Mutations of the VHL tumour suppressor gene in renal carcinoma.Nat Genet 7:85–90, 1994.

    Article  PubMed  CAS  Google Scholar 

  59. Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, Nagashima Y, Kitamura H, Latif F, Zbar B,et al: Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas.Cancer Res 54:2852–2855, 1994.

    PubMed  CAS  Google Scholar 

  60. Olschwang S, Richard S, Boisson C, Giraud S, Lau-rent-Puig P, Resche F, Thomas G: Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.Hum Mutat 12:424–430, 1998.

    Article  PubMed  CAS  Google Scholar 

  61. Semenza GL: HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus.Cell 107:1–3, 2001.

    Article  PubMed  CAS  Google Scholar 

  62. Vaupel P, Kallinowski F, Okunieff P: Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review.Cancer Res 49:6449–6465, 1989.

    PubMed  CAS  Google Scholar 

  63. Dang CV, Semenza GL: Oncogenic alterations of metabolism.Trends Biochem Sci 24:68–72, 1999.

    Article  PubMed  CAS  Google Scholar 

  64. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol 16:4604–4613, 1996.

    PubMed  CAS  Google Scholar 

  65. Semenza GL, Roth PH, Fang HM, Wang GL: Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.J Biol Chem 269:23757–23763, 1994.

    PubMed  CAS  Google Scholar 

  66. Zhong H, Marzo De AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Overexpression of hypoxia-inducible factor lalpha in common human cancers and their metastases.Cancer Res 59:5830–5835, 1999.

    PubMed  CAS  Google Scholar 

  67. Brown JM: The hypoxic cell: a target for selective cancer therapy-eighteenth Bruce F. Cain Memorial Award lecture.Cancer Res 59:5863–5870, 1999.

    PubMed  CAS  Google Scholar 

  68. Semenza GL: Targeting HIF-1 for cancer therapy.Nat Rev Cancer 3:721–732, 2003.

    Article  PubMed  CAS  Google Scholar 

  69. Birner P, Gatterbauer B, Oberhuber G, Schindl M, Rossler K, Prodinger A, Budka H, Hainfellner JA: Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis.Cancer 92:165–171, 2001.

    Article  PubMed  CAS  Google Scholar 

  70. Schindl M, Schoppmann SF, Samonigg H, Haus-maninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G; Austrian Breast and Colorectal Cancer Study Group: Overexpression of hypoxia-inducible factor lalpha is associated with an unfavorable prognosis in lymph node-positive breast cancer.Clin Cancer Res 8:1831–1837, 2002.

    PubMed  CAS  Google Scholar 

  71. Birner P, Schindl M, Obermair A, Plank C, Breite-necker G, Oberhuber G: Overexpression of hypoxia-inducible factor lalpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer.Cancer Res 60:4693–4696, 2000.

    PubMed  CAS  Google Scholar 

  72. Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M: Tumor hypoxia: A target for selective cancer therapy.Cancer Sci 94:1021–1028, 2003.

    Article  PubMed  CAS  Google Scholar 

  73. Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS het-erodimer regulated by cellular 02 tension.Proc Natl Acad Sci USA 92:5510–5514, 1995.

    Article  PubMed  CAS  Google Scholar 

  74. Zhao M, Weissleder R: Intracellular cargo delivery using tat peptide and derivatives.Med Res Rev 24:1–12, 2004.

    Article  PubMed  Google Scholar 

  75. Dietz GP, Bahr M: Delivery of bioactive molecules into the cell: the Trojan horse approach.Mol Cell Neurosci 27:85–131, 2004.

    Article  PubMed  CAS  Google Scholar 

  76. Gaizo Del V, Payne RM: A novel TAT-mitochondrial signal sequence fusion protein is processed, stays in mitochondria, and crosses the placenta.Mol Ther 7:720–730, 2003.

    Article  PubMed  Google Scholar 

  77. Chen YN, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW, Kaelin WG Jr: Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists.Proc Natl Acad Sci USA 96:4325–4329, 1999.

    Article  PubMed  CAS  Google Scholar 

  78. Pusztai L, Ayers M, Stec J, Clark E, Hess K, Stivers D, Damokosh A, Sneige N, Buchholz TA, Esteva FJ, Arun B, Cristofanilli M, Booser D, Rosales M, Valero V, Adams C, Hortobagyi GN, Symmans WF: Gene expression profiles obtained from fine-needle aspirations of breast cancer reliably identify routine prognostic markers and reveal large-scale molecular differences between estrogen-negative and estrogen-positive tumors.Clin Cancer Res 9:2406–2415, 2003.

    PubMed  CAS  Google Scholar 

  79. Lipponen P: Apoptosis in breast cancer: relationship with other pathological parameters.Endocr Relat Cancer 6:13–16, 1999.

    Article  PubMed  CAS  Google Scholar 

  80. Lipponen PK, Aaltomaa S: Apoptosis in bladder cancer as related to standard prognostic factors and prognosis.J Pathol 173:333–339, 1994.

    Article  PubMed  CAS  Google Scholar 

  81. Lipponen P, Aaltomaa S, Kosma VM, Syrjanen K: Apoptosis in breast cancer as related to histopatho-logical characteristics and prognosis.Eur J Cancer 30A:2068–2073, 1994.

    Article  PubMed  CAS  Google Scholar 

  82. Zhang GJ, Kimijima I, Abe R, Watanabe T, Kanno M, Hara K, Tsuchiya A: Apoptotic index correlates to bcl-2 and p53 protein expression, histological grade and prognosis in invasive breast cancers.Anticancer Res 18:1989–1998, 1998.

    PubMed  CAS  Google Scholar 

  83. Martinez A, Walker RA, Shaw JA, Dearing SJ, Maher ER, Latif F: Chromosome 3p allele loss in early invasive breast cancer: detailed mapping and association with clinicopathological features.Mol Pathol 54:300–306, 2001.

    Article  PubMed  CAS  Google Scholar 

  84. Vaupel P, Schlenger K, Knoop C, Hockel M: Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized 02 tension measurements.Cancer Res 51:3316–3322, 1991.

    PubMed  CAS  Google Scholar 

  85. Hohenberger P, Feigner C, Haensch W, Schlag PM: Tumor oxygenation correlates with molecular growth determinants in breast cancer.Breast Cancer Res Treat 48:97–106, 1998.

    Article  PubMed  CAS  Google Scholar 

  86. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, Diest van PJ, Wall van der E: Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis.J Natl Cancer Inst 93:309–314, 2001.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, 606-8507, Kyoto, Japan

    Hiroshi Harada, Shinae Kizaka-Kondoh & Masahiro Hiraoka

  2. Kyoto City Collaboration of Regional Entities for the Advancement of Technological Excellence, Japan Science and Technology Agency, Japan

    Hiroshi Harada

  3. COE formation for genomic analysis of disease model animals with multiple genetic alterations, Kyoto University Graduate School of Medicine, Japan

    Shinae Kizaka-Kondoh

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  1. Hiroshi Harada
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  2. Shinae Kizaka-Kondoh
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  3. Masahiro Hiraoka
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Correspondence to Hiroshi Harada.

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Harada, H., Kizaka-Kondoh, S. & Hiraoka, M. Antitumor protein therapy; Application of the protein transduction domain to the development of a protein drug for cancer treatment. Breast Cancer 13, 16–26 (2006). https://doi.org/10.2325/jbcs.13.16

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