The complexity of the HIF-1-dependent hypoxic response in breast cancer presents multiple avenues for therapeutic intervention

Pharmaceutical Perspectives of Cancer Therapeutics

Volumn , Issue , 2009, Pages 521-558

  Seagroves, Tiffany N ^a  

^a UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84900149711     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-4419-0131-6_16     Document Type: Chapter

References (228)

1. Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998;58:1408-1416.
2. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev 2000;14:1983-1991.
3. Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Borresen-Dale AL, Giaccia A, Longaker MT, Hastie T, Yang GP, van de Vijver MJ, Brown PO. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 2006;3:e47.
4. Goonewardene TI, Sowter HM, Harris AL. Hypoxia-induced pathways in breast cancer. Microsc Res Tech 2002;59:41-48.
5. Greijer AE, van der Groep P, Kemming D, Shvarts A, Semenza GL, Meijer GA, van de Wiel MA, Belien JA, van Diest PJ, van der Wall E. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 2005;206:291-304.
6. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Issacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1a in common human cancers and their metastases. Cancer Res 1999;59:5830-5835.
7. Bos R, Zhong H, Hanrahan CF, Mommers E, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1a during breast carcinogenesis. J Natl Cancer Inst 2001;93:309-314.
8. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 2003;97:1573-1581.
9. Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S, Bersiga A, Allevi G, Milani M, Aguggini S, Gandolfi V, Dogliotti L, Bottini A, Harris AL, Fox SB. Hypoxiainducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res 2006;12:4562-4568.
10. Gruber G, Greiner RH, Hlushchuk R, Aebersold DM, Altermatt HJ, Berclaz G, Djonov V. Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter? Breast Cancer Res 2004;6:R191-R198.
11. Yamamoto Y, Ibusuki M, Okumura Y, Kawasoe T, Kai K, Iyama K, Iwase H. Hypoxiainducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat 2008;110:465-475.
12. Dales JP, Garcia S, Meunier-Carpentier S, Andrac-Meyer L, Haddad O, Lavaut MN, Allasia C, Bonnier P, Charpin C. Overexpression of hypoxia-inducible factor HIF-1alpha predicts early relapse in breast cancer: retrospective study in a series of 745 patients. Int J Cancer 2005;116:734-739.
13. Brown JM. Tumor hypoxia in cancer therapy. Methods Enzymol 2007;435:297-321.
14. Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 2007;99:1441-1454.
15. Stoner M, Saville B, Wormke M, Dean D, Burghardt R, Safe S. Hypoxia induces proteasome-dependent degradation of estrogen receptor alpha in ZR-75 breast cancer cells. Mol Endocrinol 2002;16:2231-2242.
16. Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell 2007;129:465-472.
17. Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, Ewald AJ, Pai SY, Ho IC, Werb Z. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 2008;13:141-152.
18. Liu JC, Deng T, Lehal RS, Kim J, Zacksenhaus E. Identification of tumorsphere- and tumor-initiating cells in HER2/Neu-induced mammary tumors. Cancer Res 2007;67:8671-8681.
19. Vaillant F, Asselin-Labat ML, Shackleton M, Forrest NC, Lindeman GJ, Visvader JE. The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res 2008;68:7711-7717.
20. Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L. Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res 2008;10:R10.
21. Cao X, Bloomston M, Zhang T, Frankel WL, Jia G, Wang B, Hall NC, Koch RM, Cheng H, Knopp MV, Sun D. Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor. Clin Cancer Res 2008;14:1831-1839.
22. Chen MS, Woodward WA, Behbod F, Peddibhotla S, Alfaro MP, Buchholz TA, Rosen JM. Wnt/beta-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. J Cell Sci 2007;120:468-477.
23. Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM. WNT/betacatenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA 2007;104:618-623.
24. Cancer facts and figures, 2008. American Cancer Society: Atlanta, 2008.
25. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 1998;8:588-594.
26. Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M, Candinas D. HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. Faseb J 2001;15:2445-2453.
27. Vaupel P, Hockel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007;9:1221-1235.
28. Kenneth NS, Rocha S. Regulation of gene expression by hypoxia. Biochem J 2008;414:19-29.
29. Maynard MA, Ohh M. Von Hippel-Lindau tumor suppressor protein and hypoxiainducible factor in kidney cancer. Am J Nephrol 2004;24:1-13.
30. Zia MK, Rmali KA, Watkins G, Mansel RE, Jiang WG. The expression of the von Hippel-Lindau gene product and its impact on invasiveness of human breast cancer cells. Int J Mol Med 2007;20:605-611.
31. Koh MY, Darnay BG, Powis G. HAF, a novel E3-ubiquitin ligase, binds and ubiquitinates HIF-1{alpha} leading to its oxygen-independent degradation. Mol Cell Biol 2008.
32. Metzen E, Ratcliffe PJ. HIF hydroxylation and cellular oxygen sensing. Biol Chem 2004;385:223-230.
33. Hu CJ, Iyer S, Sataur A, Covello KL, Chodosh LA, Simon MC. Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol 2006;26:3514-3526.
34. Hu CJ, Sataur A, Wang L, Chen H, Simon MC. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell 2007;18:4528-4542.
35. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxiainducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 2003;23:9361-9374.
36. Sowter HM, Raval RR, Moore JW, Ratcliffe PJ, Harris AL. Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 2003;63:6130-6134.
37. Wang V, Davis DA, Haque M, Huang LE, Yarchoan R. Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells. Cancer Res 2005;65:3299-3306.
38. Warnecke C, Weidemann A, Volke M, Schietke R, Wu X, Knaup KX, Hackenbeck T, Bernhardt W, Willam C, Eckardt KU, Wiesener MS. The specific contribution of hypoxia-inducible factor-2alpha to hypoxic gene expression in vitro is limited and modulated by cell type-specific and exogenous factors. Exp Cell Res 2008;314:2016-2027.
39. Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, Eckardt KU. Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. Faseb J 2004;18:1462-1464.
40. Wiesener MS, Jurgensen JS, Rosenberger C, Scholze CK, Horstrup JH, Warnecke C, Mandriota S, Bechmann I, Frei UA, Pugh CW, Ratcliffe PJ, Bachmann S, Maxwell PH, Eckardt KU. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. Faseb J 2003;17:271-273.
41. Seagroves T, Johnson RS. Two HIFs may be better than one. Cancer Cell 2002;1:211-213.
42. Maynard MA, Qi H, Chung J, Lee EH, Kondo Y, Hara S, Conaway RC, Conaway JW, Ohh M. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem 2003;278:11032-11040.
43. Blancher C, Moore JW, Talks KL, Houlbrook S, Harris AL. Relationship of hypoxiainducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res 2000;60:7106-7113.
44. Helczynska K, Larsson A-M, Mengelbier L, Bridges E, Fredlund E, Borgquist S, Landberg G, Pahlman S, Jirstrom K. Hypoxia-Inducible Factor-2alpha correlates to distant recurrence and poor outcome in invasvive breast cancer. Cancer Res 2008;68:9212-9220.
45. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. Embo J 1998;17:3005-3015.
46. Nagy A. Cre recombinase: the universal reagent for genome tailoring. Genesis 2000;26:99-109.
47. Doedens A, Johnson RS. Transgenic models to understand hypoxia-inducible factor function. Methods Enzymol 2007;435:87-105.
48. Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res 2000;60:4010-4015.
49. Wagner KU, Wall RJ, St-Onge L, Gruss P, Wynshaw-Boris A, Garrett L, Li M, Furth PA, Hennighausen L. Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res 1997;25:4323-4330.
50. Wagner KU, McAllister K, Ward T, Davis B, Wiseman R, Hennighausen L. Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 2001;10:545-553.
51. Seagroves TN, Hadsell D, McManaman J, Palmer C, Liao D, McNulty W, Welm B, Wagner KU, Neville M, Johnson RS. HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland. Development 2003;130:1713-1724.
52. Anderson SM, Rudolph MC, McManaman JL, Neville MC. Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis! Breast Cancer Res 2007;9:204.
53. Saarikoski ST, Rivera SP, Hankinson O. Mitogen-inducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia. FEBS Lett 2002;530:186-190.
54. Vorbach C, Scriven A, Capecchi MR. The housekeeping gene xanthine oxidoreductase is necessary for milk fat droplet enveloping and secretion: gene sharing in the lactating mammary gland. Genes Dev 2002;16:3223-3235.
55. Russell TD, Palmer CA, Orlicky DJ, Fischer A, Rudolph MC, Neville MC, McManaman JL. Cytoplasmic lipid droplet accumulation in developing mammary epithelial cells: roles of adipophilin and lipid metabolism. J Lipid Res 2007;48:1463-1475.
56. Cardiff RD. Validity of mouse mammary tumour models for human breast cancer: comparative pathology. Microsc Res Tech 2001;52:224-230.
57. Wagner KU. Models of breast cancer: quo vadis, animal modeling? Breast Cancer Res 2004;6:31-38.
58. Desai KV, Xiao N, Wang W, Gangi L, Greene J, Powell JI, Dickson R, Furth P, Hunter K, Kucherlapati R, Simon R, Liu ET, Green JE. Initiating oncogenic event determines geneexpression patterns of human breast cancer models. Proc Natl Acad Sci USA 2002;99:6967-6972.
59. Qiu TH, Chandramouli GV, Hunter KW, Alkharouf NW, Green JE, Liu ET. Global expression profiling identifies signatures of tumor virulence in MMTV-PyMT-transgenic mice: correlation to human disease. Cancer Res 2004;64:5973-5981.
60. Barnes DM, Bartkova J, Camplejohn RS, Gullick WJ, Smith PJ, Millis RR. Overexpression of the c-erbB-2 oncoprotein: why does this occur more frequently in ductal carcinoma in situ than in invasive mammary carcinoma and is this of prognostic significance? Eur J Cancer 1992;28:644-648.
61. Cardiff RD, Wagner U, Hennighausen L. Mammary cancer in humans and mice: a tutorial for comparative pathology. Vet Pathol 2001;38:357-358.
62. Rosner A, Miyoshi K, Landesman-Bollag E, Xu X, Seldin DC, Moser AR, MacLeod CL, Shyamala G, Gillgrass AE, Cardiff RD. Pathway pathology: histological differences between ErbB/Ras and Wnt pathway transgenic mammary tumors. Am J Pathol 2002;161:1087-1097.
63. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 2003;163:2113-2126.
64. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 2007;8:R76.
65. Liao D, Corle C, Seagroves TN, Johnson RS. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 2007;67:563-572.
66. Bilton RL, Booker GW. The subtle side to hypoxia inducible factor (HIFalpha) regulation. Eur J Biochem 2003;270:791-798.
67. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 1999;59:3915-3918.
68. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001;21:3995-4004.
69. Tanaka H, Yamamoto M, Hashimoto N, Miyakoshi M, Tamakawa S, Yoshie M, Tokusashi Y, Yokoyama K, Yaginuma Y, Ogawa K. Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis. Cancer Res 2006;66:11263-11270.
70. Gort EH, Groot AJ, Derks van de Ven TL, van der Groep P, Verlaan I, van Laar T, van Diest PJ, van der Wall E, Shvarts A. Hypoxia-inducible factor-1alpha expression requires PI 3-kinase activity and correlates with Akt1 phosphorylation in invasive breast carcinomas. Oncogene 2006;25:6123-6127.
71. Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem 2006;281:25903-25914.
72. Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, Hung MC. Survival of cancer cells is maintained by EGFRindependent of its kinase activity. Cancer Cell 2008;13:385-393.
73. Vega C, R. Sachleben L J, Gozal D, Gozal E. Differential metabolic adaptation to acute and long-term hypoxia in rat primary cortical astrocytes. J Neurochem 2006;97:872-883.
74. Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res 2006;66:3197-3204.
75. Lu Y, Liang K, Li X, Fan Z. Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1alpha. Mol Cancer 2007;6:63.
76. de Paulsen N, Brychzy A, Fournier MC, Klausner RD, Gnarra JR, Pause A, Lee S. Role of transforming growth factor-alpha in von Hippel-Lindau (VHL) (-/-) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci USA 2001;98:1387-1392.
77. Semenza GL. Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today 2007;12:853-859.
78. Giordano F, Johnson R. Angiogenesis: the role of the microenvironment in flipping the switch. Curr Opin Genet Dev 2001;11:35-40.
79. Krek W. VHL takes HIF's breath away. Nat Cell Biol 2000;2:E121-E123.
80. Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 2002;1:193-202.
81. Bando H. Vascular endothelial growth factor and bevacitumab in breast cancer. Breast Cancer 2007;14:163-173.
82. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 2004;165:35-52.
83. Mancuso MR, Davis R, Norberg SM, O'Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006;116:2610-2621.
84. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58-62.
85. Fukumura D, Jain RK. Tumor microvasculature and microenvironment: targets for antiangiogenesis and normalization. Microvasc Res 2007;74:72-84.
86. Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, Matsubara I, Vinante O, Bonoldi E, Boracchi P, Gatti C, Suzuki H, Tominaga T. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 1997;89:139-147.
87. Gasparini G, Toi M, Verderio P, Ranieri G, Dante S, Bonoldi E, Boracchi P, Fanelli M, Tominaga T. Prognostic significance of p53, angiogenesis, and other conventional features in operable breast cancer: subanalysis in node-positive and node-negative patients. Int J Oncol 1998;12:1117-1125.
88. Koukourakis MI, Manolas C, Minopoulos G, Giatromanolaki A, Sivridis E. Angiogenesis relates to estrogen receptor negativity, c-erbB-2 overexpression and early relapse in node-negative ductal carcinoma of the breast. Int J Surg Pathol 2003;11:29-34.
89. Tsutsui S, Kume M, Era S. Prognostic value of microvessel density in invasive ductal carcinoma of the breast. Breast Cancer 2003;10:312-319.
90. Bos R, van Diest PJ, de Jong JS, van derGroep P, van der Valk P, van derWall E. Hypoxiainducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGFBB, and EGFR in invasive breast cancer. Histopathology 2005;46:31-36.
91. Oehler-Janne C, Jochum W, Riesterer O, Broggini-Tenzer A, Caravatti G, Vuong V, Pruschy M. Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models. Mol Cancer Ther 2007;6:2496-2504.
92. Carmeliet P, Dor Y, Herbert J, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshet E. Role of HIF-1alpha in hypoxia mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998;394:485-490.
93. Rossiter H, Barresi C, Ghannadan M, Gruber F, Mildner M, Fodinger D, Tschachler E. Inactivation of VEGF in mammary gland epithelium severely compromises mammary gland development and function. Faseb J 2007;21:3994-4004.
94. Warburg O. The Metabolism of Tumours. Constable & Co., Ltd.: London, 1930.
95. Hamilton E, Fennell M, Stafford DM. Modification of tumour glucose metabolism for therapeutic benefit. Acta Oncol 1995;34:429-433.
96. Seagroves T, Ryan HE, Lu H, Wouters BG, Knapp AM, Thibault P, Laderoute KR, Johnson RS. The transcription factor HIF-1 is a necessary mediator of the Pasteur effect in mammalian cells. Mol Cell Biol 2001;21:3436-3444.
97. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 2003;112:645-657.
98. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS. Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 2004;6:485-495.
99. Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ. Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors. Neoplasia 2005;7:324-330.
100. Robey IF, Stephen RM, Brown KS, Baggett BK, Gatenby RA, Gillies RJ. Regulation of the Warburg effect in early-passage breast cancer cells. Neoplasia 2008;10:745-756.
101. Maher JC, Wangpaichitr M, Savaraj N, Kurtoglu M, Lampidis TJ. Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. Mol Cancer Ther 2007;6:732-741.
102. Mazurek S, Weisse G, Wust G, Schafer-Schwebel A, Eigenbrodt E, Friis RR. Energy metabolism in the involuting mammary gland. In Vivo 1999;13:467-478.
103. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127:679-695.
104. Woelfle U, Cloos J, Sauter G, Riethdorf L, Janicke F, van Diest P, Brakenhoff R, Pantel K. Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 2003;63:5679-5684.
105. Pierga JY, Bonneton C, Magdelenat H, Vincent-Salomon A, Nos C, Pouillart P, Thiery JP. Clinical significance of proliferative potential of occult metastatic cells in bone marrow of patients with breast cancer. Br J Cancer 2003;89:539-545.
106. Luker KE, Luker GD. Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett 2006;238:30-41.
107. Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 2005;23:879-894.
108. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005;121:335-348.
109. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004;10:858-864.
110. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003;425:307-311.
111. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006;25:977-988.
112. Kim SY, Lee CH, Midura BV, Yeung C, Mendoza A, Hong SH, Ren L, Wong D, Korz W, Merzouk A, Salari H, Zhang H, Hwang ST, Khanna C, Helman LJ. Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis 2008;25:201-211.
113. Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, Luker GD. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 2004;64:8604-8612.
114. Payne SL, Fogelgren B, Hess AR, Seftor EA, Wiley EL, Fong SF, Csiszar K, Hendrix MJ, Kirschmann DA. Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res 2005;65:11429-11436.
115. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 2008;105(17):6392-6397.
116. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006;440:1222-1226.
117. Tse JC, Kalluri R. Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 2007;101:816-829.
118. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004;117:927-939.
119. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 2008;10:295-305.
120. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007;7:415-428.
121. Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, Kim WY, Saravanan A, Maynard MA, Gervais ML, Sufan RI, Roberts AM, Wilson LA, Betten M, Vandewalle C, Berx G, Marsden PA, Irwin MS, Teh BT, Jewett MA, Ohh M. VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol 2007;27:157-169.
122. Zhu Y, Denhardt DT, Cao H, Sutphin PD, Koong AC, Giaccia AJ, Le QT. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene 2005;24:6555-6563.
123. Sodhi CP, Phadke SA, Batlle D, Sahai A. Hypoxia stimulates osteopontin expression and proliferation of cultured vascular smooth muscle cells: potentiation by high glucose. Diabetes 2001;50:1482-1490.
124. Tuck AB, Chambers AF, Allan AL. Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management. J Cell Biochem 2007;102:859-868.
125. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003;3:537-549.
126. McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, Reinhardt F, Harris LN, Hylander BL, Repasky EA, Weinberg RA. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 2008;133:994-1005.
127. Rochefort GY, Delorme B, Lopez A, Herault O, Bonnet P, Charbord P, Eder V, Domenech J. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells 2006;24:2202-2208.
128. Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 2005;5:311-321.
129. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.
130. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100:3983-3988.
131. Morrison BJ, Schmidt CW, Lakhani SR, Reynolds BA, Lopez JA. Breast cancer stem cells: implications for therapy of breast cancer. Breast Cancer Res 2008;10:210.
132. Rich JN. Cancer stem cells in radiation resistance. Cancer Res 2007;67:8980-8984.
133. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 2007;104:5431-5436.
134. Piccoli C, D'Aprile A, Ripoli M, Scrima R, Boffoli D, Tabilio A, Capitanio N. The hypoxia-inducible factor is stabilized in circulating hematopoietic stem cells under normoxic conditions. FEBS Lett 2007;581:3111-3119.
135. Yang Z, Levison SW. Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone. Neuroscience 2006;139:555-564.
136. Li F, Tiede B, Massague J, Kang Y. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res 2007;17:3-14.
137. Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 2006;12:5615-5621.
138. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004;23:7274-7282.
139. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE. Generation of a functional mammary gland from a single stem cell. Nature 2006;439:84-88.
140. Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D, Medina D, Tsimelzon A, Hilsenbeck S, Green JE, Michalowska AM, Rosen JM. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res 2008;68:4674-4682.
141. Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, van der Wees J, Lindeman GJ, Visvader JE. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 2007;9:201-209.
142. Soeda A, Inagaki A, Oka N, Ikegame Y, Aoki H, Yoshimura S, Nakashima S, Kunisada T, Iwama T. Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem 2008;283:10958-10966.
143. Mizrak D, Brittan M, Alison MR. CD133:molecule of themoment. JPathol 2008;214:3-9.
144. Bidlingmaier S, Zhu X, Liu B. The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med 2008;86:1025-1032.
145. Platet N, Liu SY, Atifi ME, Oliver L, Vallette FM, Berger F, Wion D. Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett 2007;258:286-290.
146. Duncan AW, Rattis FM, Di Mascio LN, Congdon KL, Pazianos G, Zhao C, Yoon K, Cook JM, Willert K, Gaiano N, Reya T. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 2005;6:314-322.
147. Katoh M. Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev 2007;3:30-38.
148. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-689.
149. Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007;12:108-113.
150. Farnie G, Clarke RB. Mammary stem cells and breast cancer-role of Notch signalling. Stem Cell Rev 2007;3:169-175.
151. Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR, Lockwood G, Egan SE. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 2005;65:8530-8537.
152. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 2004;6:R605-R615.
153. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003;17:1253-1270.
154. Hu C, Dievart A, Lupien M, Calvo E, Tremblay G, Jolicoeur P. Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors. Am J Pathol 2006;168:973-990.
155. Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KM, Superti-Furga G, Pawson T, Di Fiore PP, Lanfrancone L, Pelicci PG. Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway. Embo J 1997;16:706-716.
156. Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M, Santini D, Ceccarelli C, Chieco P, Bonafe M. p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells 2007;25:807-815.
157. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 2005;9:617-628.
158. Zheng X, Linke S, Dias JM, Zheng X, Gradin K, Wallis TP, Hamilton BR, Gustafsson M, Ruas JL, Wilkins S, Bilton RL, Brismar K, Whitelaw ML, Pereira T, Gorman JJ, Ericson J, Peet DJ, Lendahl U, Poellinger L. Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. Proc Natl Acad Sci USA 2008;105:3368-3373.
159. Lee CW, Raskett CM, Prudovsky I, Altieri DC. Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis. Cancer Res 2008;68:5273-5281.
160. Tan EY, Campo L, Han C, Turley H, Pezzella F, Gatter KC, Harris AL, Fox SB. Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer. Breast Cancer Res 2007;9:R89.
161. Imbert A, Eelkema R, Jordan S, Feiner H, Cowin P. Delta N89 beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland. J Cell Biol 2001;153:555-568.
162. Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM, Varmus HE. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci USA 2003;100:15853-15858.
163. Tepera SB, McCrea PD, Rosen JM. Abeta-catenin survival signal is required for normal lobular development in the mammary gland. J Cell Sci 2003;116:1137-1149.
164. Flugel D, Gorlach A, Michiels C, Kietzmann T. Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. Mol Cell Biol 2007;27:3253-3265.
165. Kaidi A, Williams AC, Paraskeva C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 2007;9:210-217.
166. Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI, Bharti A, Seldin DC, Lecker SH, Dominguez I, Cohen HT. Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol 2008;10:1208-1216.
167. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002;62:3387-3394.
168. Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, Dewhirst MW. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005;8:99-110.
169. Williams KJ, Telfer BA, Xenaki D, Sheridan MR, Desbaillets I, Peters HJ, Honess D, Harris AL, Dachs GU, van der Kogel A, Stratford IJ. Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiother Oncol 2005;75:89-98.
170. Song X, Liu X, Chi W, Liu Y, Wei L, Wang X, Yu J. Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol 2006;58:776-784.
171. Hussein D, Estlin EJ, Dive C, Makin GW. Chronic hypoxia promotes hypoxia-inducible factor-1alpha-dependent resistance to etoposide and vincristine in neuroblastoma cells. Mol Cancer Ther 2006;5:2241-2250.
172. Zeng L, Kizaka-Kondoh S, Itasaka S, Xie X, Inoue M, Tanimoto K, Shibuya K, Hiraoka M. Hypoxia inducible factor-1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions. Cancer Sci 2007;98:1394-1401.
173. Hao J, Song X, Song B, Liu Y, Wei L, Wang X, Yu J. Effects of lentivirus-mediated HIF-1alpha knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells. Cancer Gene Ther 2008;15:449-455.
174. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004;5:429-441.
175. Martinive P, Defresne F, Bouzin C, Saliez J, Lair F, Gregoire V, Michiels C, Dessy C, Feron O. Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications for anticancer therapies. Cancer Res 2006;66:11736-11744.
176. Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van denHoogen FJ, de Wilde PC, Bussink J, Raleigh JA, van der Kogel AJ. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res 2002;62:7066-7074.
177. Eriksen JG, Overgaard J. Lack of prognostic and predictive value of CA IX in radiotherapy of squamous cell carcinoma of the head and neck with known modifiable hypoxia: an evaluation of the DAHANCA 5 study. Radiother Oncol 2007;83:383-388.
178. Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 2008;8:545-554.
179. Phillips TM, McBride WH, Pajonk F. The response of CD24 (-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 2006;98:1777-1785.
180. Wardman P. Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia. Curr Med Chem 2001;8:739-761.
181. Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sarkadi B, Sorrentino BP, Schuetz JD. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 2004;279:24218-24225.
182. Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA. Sca-1 (pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 2002;245:42-56.
183. Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 2001;7:1028-1034.
184. Cooper C, Liu GY, Niu YL, Santos S, Murphy LC, Watson PH. Intermittent hypoxia induces proteasome-dependent down-regulation of estrogen receptor alpha in human breast carcinoma. Clin Cancer Res 2004;10:8720-8727.
185. Kurebayashi J, Otsuki T, Moriya T, Sonoo H. Hypoxia reduces hormone responsiveness of human breast cancer cells. Jpn J Cancer Res 2001;92:1093-1101.
186. Kronblad A, Helczynska K, Nielsen NH, Pahlman E, Emdin S, Pahlman S, Landberg G. Regional cyclin D1 overexpression or hypoxia correlate inversely with heterogeneous oestrogen receptor-alpha expression in human breast cancer. In Vivo 2003;17:311-318.
187. Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M. Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res 1995;55:3331-3338.
188. Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS. Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 2003;144:4562-4574.
189. Diaz-Gonzalez JA, Russell J, Rouzaut A, Gil-Bazo I, Montuenga L. Targeting hypoxia and angiogenesis through HIF-1alpha inhibition. Cancer Biol Ther 2005;4:1055-1062.
190. Luwor RB, Lu Y, Li X, Mendelsohn J, Fan Z. The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 2005;24:4433-4441.
191. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006;66:5549-5554.
192. Mosley JD, Poirier JT, Seachrist DD, Landis MD, Keri RA. Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer. Mol Cancer Ther 2007;6:2188-2197.
193. Albert JM, Kim KW, Cao C, Lu B. Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 2006;5:1183-1189.
194. Blancher C, Moore JW, Robertson N, Harris AL. Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 30-kinase/Akt signaling pathway. Cancer Res 2001;61:7349-7355.
195. http://clinicaltrials.gov
196. Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD, Iwata KK, Gibson NW, Griffin G. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 2006;5:2676-2684.
197. Wang LH, Chan JL, Li W. Rapamycin together with herceptin significantly increased anti-tumor efficacy compared to either alone in ErbB2 over expressing breast cancer cells. Int J Cancer 2007;121:157-164.
198. Johnson AB, Denko N, Barton MC. Hypoxia induces a novel signature of chromatin modifications and global repression of transcription. Mutat Res 2008;640:174-179.
199. Okazaki K, Maltepe E. Oxygen, epigenetics and stemcell fate. RegenMed 2006;1:71-83.
200. MieLee Y, Kim SH, Kim HS, Jin Son M, Nakajima H, JeongKwon H, Kim KW. Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. Biochem Biophys Res Commun 2003;300:241-246.
201. Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P, Pili R. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 2006;66:8814-8821.
202. Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 2004;64:1475-1482.
203. Wolff AC, O'Neill A, Kennedy MJ, Stewart JA, Gradishar WJ, Lord RS, 3rd, Davidson NE, Wood WC. Single-agent topotecan as first-line chemotherapy in women with metastatic breast cancer: final results of eastern cooperative oncology group trial E8193. Clin Breast Cancer 2005;6:334-339.
204. Neckers L. Heat shock protein 90: the cancer chaperone. J Biosci 2007;32:517-530.
205. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ. A highaffinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003;425:407-410.
206. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 2002;277:29936-29944.
207. Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL. RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O (2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell 2007;25:207-217.
208. Solit DB, Ivy SP, Kopil C, Sikorski R, Morris MJ, Slovin SF, Kelly WK, De LaCruz A, Curley T, Heller G, Larson S, Schwartz L, Egorin MJ, Rosen N, Scher HI. Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Clin Cancer Res 2007;13:1775-1782.
209. Sawai A, Chandarlapaty S, Greulich H, Gonen M, Ye Q, Arteaga CL, Sellers W, Rosen N, Solit DB. Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel. Cancer Res 2008;68:589-596.
210. Pashtan I, Tsutsumi S, Wang S, Xu W, Neckers L. Targeting Hsp90 prevents escape of breast cancer cells from tyrosine kinase inhibition. Cell Cycle 2008;7:2936-2941.
211. Chandarlapaty S, Sawai A, Ye Q, Scott A, Silinski M, Huang K, Fadden P, Partdrige J, Hall S, Steed P, Norton L, Rosen N, Solit DB. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res 2008;14:240-248.
212. Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. JNatlCancer Inst 2003;95:516-525.
213. Shin DH, Kim JH, Jung YJ, Kim KE, Jeong JM, Chun YS, Park JW. Preclinical evaluation of YC-1, a HIF inhibitor, for the prevention of tumor spreading. Cancer Lett 2007;255:107-116.
214. Hiraga T, Kizaka-Kondoh S, Hirota K, Hiraoka M, Yoneda T. Hypoxia and hypoxiainducible factor-1 expression enhance osteolytic bone metastases of breast cancer. Cancer Res 2007;67:4157-4163.
215. Chen CJ, Hsu MH, Huang LJ, Yamori T, Chung JG, Lee FY, Teng CM, Kuo SC. Anticancer mechanisms of YC-1 in human lung cancer cell line, NCI-H226. Biochem Pharmacol 2008;75:360-368.
216. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther 2004;3:233-244.
217. Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther 2008;7:90-100.
218. Dervan PB, Doss RM, Marques MA. Programmable DNA binding oligomers for control of transcription. Curr Med Chem Anticancer Agents 2005;5:373-387.
219. Olenyuk BZ, Zhang GJ, Klco JM, Nickols NG, Kaelin WG, Jr, Dervan PB. Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci USA 2004;101:16768- 16773.
220. Nickols NG, Jacobs CS, Farkas ME, Dervan PB. Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface. ACS Chem Biol 2007;2:561-571.
221. Black MM, Kleiner IS, Bolker H. Glycolytic enzyme inhibitor therapy in human malignant neoplasia. Cancer Res 1949;9:314-319.
222. Mohanti BK, Rath GK, Anantha N, Kannan V, Das BS, Chandramouli BA, Banerjee AK, Das S, Jena A, Ravichandran R, Sahi UP, Kumar R, Kapoor N, Kalia VK, Dwarakanath BS, Jain V. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys 1996;35:103-111.
223. Coleman MC, Asbury CR, Daniels D, Du J, Aykin-Burns N, Smith BJ, Li L, Spitz DR, Cullen JJ. 2-deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer. Free Radic Biol Med 2008;44:322-331.
224. Simons AL, Ahmad IM, Mattson DM, Dornfeld KJ, Spitz DR. 2-Deoxy-D-glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells. Cancer Res 2007;67:3364-3370.
225. Haga N, Naito M, Seimiya H, Tomida A, Dong J, Tsuruo T. 2-Deoxyglucose inhibits chemotherapeutic drug-induced apoptosis in human monocytic leukemia U937 cells with inhibition of c-Jun. N-terminal kinase 1/stress-activated protein kinase activation. Int J Cancer 1998;76:86-90.
226. Harada H, Kizaka-Kondoh S, Li G, Itasaka S, Shibuya K, Inoue M, Hiraoka M. Significance of HIF-1-active cells in angiogenesis and radioresistance. Oncogene 2007;26(54):7508-7516.
227. Perret GY, Crepin M. New pharmacological strategies against metastatic spread. Fundam Clin Pharmacol 2008;22:465-492.
228. Raleigh JA, Koch CJ. Importance of thiols in the reductive binding of 2-nitroimidazoles to macromolecules. Biochem Pharmacol 1990;40:2457-2464.