J Breast Cancer.  2011 Sep;14(3):167-174.

Heat Shock Protein as Molecular Targets for Breast Cancer Therapeutics

Affiliations
  • 1Division of Breast and Endocrine Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea. lskim0503@hallym.ac.kr

Abstract

Recent advances in the understanding of the molecular mechanisms involved in the breast cancer development and progression have led to the identification of numerous novel molecular targets. Among these, heat shock proteins (HSPs) are being emerging molecular target due to its diverse function in cancer cells. HSPs are highly conserved molecular chaperone that are synthesized by cell in response to various stress conditions. Mammalian HSPs have been classified into several families according to their molecular weight: HSP100, HSP90, HSP72, and small molecular HSPs (including HSP27). They are essential proteins that play a key role in cell survival through the cytoprotective mechanisms. In addition, HSPs are often overexpressed in a rage of cancers including breast cancer, and its overexpression seems to be associated with poor clinical outcomes. Also, HSP90 play a role in facilitating transformation by stabilizing the mutated and overexpressed oncoproteins found in breast cancer cell. Pharmacological targeting of HSP is therefore indicated and in the case of HSP90, numerous inhibitory drugs are undergoing clinical trial for treatment of breast cancer and other cancers. In this review, we describe the roles of HSPs in cancer cell and introduce the HSPs inhibitor as molecular target in cancer therapy and its recent clinical trials in breast cancer.

Keyword

Breast; Carcinoma; Chaperone; Heat; Shock

MeSH Terms

Breast
Breast Neoplasms
Cell Survival
Heat-Shock Proteins
Hot Temperature
Humans
Molecular Chaperones
Oncogene Proteins
Proteins
Rage
Shock
Heat-Shock Proteins
Molecular Chaperones
Oncogene Proteins
Proteins

Figure

  • Figure 1 HSP70/90 expression on breast cancer cell lines using Western blot assay. Expression of HSP70/90 are observated in both hormone receptor positive cell lines (1: MDA-MB 435; 2: MDA-MB 231) and hormone receptor negative cell lines (6: MCF-7; 7: T-47D). Also, MDA-MB 231LC3 (3), MDA-MB 231GFP (4), and MDA-MB 231BR3 cell line (5) expressed HSP70/90 proteins.

  • Figure 2 The effect of geldanamycin on breast cancer cell lines measured by MTT assay. Compared with DMSO and control group, gendanamycin markedly inhibited the cell growth in breast cancer cell lines in a dose-dependent manner.


Reference

1. Workman P. Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett. 2004. 206:149–157.
Article
2. Workman P, Burrows F, Neckers L, Rosen N. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci. 2007. 1113:202–216.
Article
3. Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med. 2002. 8:4 Suppl. S55–S61.
Article
4. Ritossa F. A new puffing pattern induced by temperature shock and DNP in drosophila. Cell Mol Life Sci. 1962. 18:571–573.
Article
5. Ritossa F. Discovery of the heat shock response. Cell Stress Chaperones. 1996. 1:97–98.
Article
6. Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005. 5:761–772.
Article
7. Welch WJ. The role of heat-shock proteins as molecular chaperones. Curr Opin Cell Biol. 1991. 3:1033–1038.
Article
8. Welch WJ, Feramisco JR. Purification of the major mammalian heat shock proteins. J Biol Chem. 1982. 257:14949–14959.
Article
9. Wu C. Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol. 1995. 11:441–469.
Article
10. Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet. 1988. 22:631–677.
Article
11. Dai C, Whitesell L, Rogers AB, Lindquist S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell. 2007. 130:1005–1018.
Article
12. Min JN, Huang L, Zimonjic DB, Moskophidis D, Mivechi NF. Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors. Oncogene. 2007. 26:5086–5097.
Article
13. Meng L, Gabai VL, Sherman MY. Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis. Oncogene. 2010. 29:5204–5213.
Article
14. Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002. 295:1852–1858.
Article
15. Ciocca DR, Oesterreich S, Chamness GC, McGuire WL, Fuqua SA. Biological and clinical implications of heat shock protein 27,000 (Hsp27): a review. J Natl Cancer Inst. 1993. 85:1558–1570.
Article
16. Sreedhar AS, Kalmár E, Csermely P, Shen YF. Hsp90 isoforms: functions, expression and clinical importance. FEBS Lett. 2004. 562:11–15.
Article
17. Joly AL, Wettstein G, Mignot G, Ghiringhelli F, Garrido C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun. 2010. 2:238–247.
Article
18. Khalil AA, Kabapy NF, Deraz SF, Smith C. Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta. 2011. 1816:89–104.
Article
19. Young JC, Agashe VR, Siegers K, Hartl FU. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol. 2004. 5:781–791.
Article
20. Didelot C, Lanneau D, Brunet M, Joly AL, De Thonel A, Chiosis G, et al. Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins. Curr Med Chem. 2007. 14:2839–2847.
Article
21. Jakob U, Gaestel M, Engel K, Buchner J. Small heat shock proteins are molecular chaperones. J Biol Chem. 1993. 268:1517–1520.
Article
22. Ciocca DR, Calderwood SK. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 2005. 10:86–103.
Article
23. Jameel A, Skilton RA, Campbell TA, Chander SK, Coombes RC, Luqmani YA. Clinical and biological significance of HSP89 alpha in human breast cancer. Int J Cancer. 1992. 50:409–415.
Article
24. Doshi BM, Hightower LE, Lee J. The role of Hsp27 and actin in the regulation of movement in human cancer cells responding to heat shock. Cell Stress Chaperones. 2009. 14:445–457.
Article
25. Arrigo AP, Paul C, Ducasse C, Manero F, Kretz-Remy C, Virot S, et al. Small stress proteins: novel negative modulators of apoptosis induced independently of reactive oxygen species. Prog Mol Subcell Biol. 2002. 28:185–204.
Article
26. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G. Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle. 2006. 5:2592–2601.
Article
27. Williams K, Chubb C, Huberman E, Giometti CS. Analysis of differential protein expression in normal and neoplastic human breast epithelial cell lines. Electrophoresis. 1998. 19:333–343.
Article
28. Myung JK, Afjehi-Sadat L, Felizardo-Cabatic M, Slavc I, Lubec G. Expressional patterns of chaperones in ten human tumor cell lines. Proteome Sci. 2004. 2:8.
29. Brunet Simioni M, De Thonel A, Hammann A, Joly AL, Bossis G, Fourmaux E, et al. Heat shock protein 27 is involved in SUMO-2/3 modification of heat shock factor 1 and thereby modulates the transcription factor activity. Oncogene. 2009. 28:3332–3344.
Article
30. Mori-Iwamoto S, Kuramitsu Y, Ryozawa S, Mikuria K, Fujimoto M, Maehara S, et al. Proteomics finding heat shock protein 27 as a biomarker for resistance of pancreatic cancer cells to gemcitabine. Int J Oncol. 2007. 31:1345–1350.
Article
31. Choi DH, Ha JS, Lee WH, Song JK, Kim GY, Park JH, et al. Heat shock protein 27 is associated with irinotecan resistance in human colorectal cancer cells. FEBS Lett. 2007. 581:1649–1656.
Article
32. Hansen RK, Parra I, Lemieux P, Oesterreich S, Hilsenbeck SG, Fuqua SA. Hsp27 overexpression inhibits doxorubicin-induced apoptosis in human breast cancer cells. Breast Cancer Res Treat. 1999. 56:187–196.
Article
33. Kang SH, Kang KW, Kim KH, Kwon B, Kim SK, Lee HY, et al. Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability. BMC Cancer. 2008. 8:286.
Article
34. Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther. 1998. 80:183–201.
Article
35. Jäättelä M. Heat shock proteins as cellular lifeguards. Ann Med. 1999. 31:261–271.
Article
36. Wang Q, He Z, Zhang J, Wang Y, Wang T, Tong S, et al. Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect Prev. 2005. 29:544–551.
Article
37. Schaffitzel E, Rüdiger S, Bukau B, Deuerling E. Functional dissection of trigger factor and DnaK: interactions with nascent polypeptides and thermally denatured proteins. Biol Chem. 2001. 382:1235–1243.
Article
38. Frydman J. Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem. 2001. 70:603–647.
Article
39. Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood). 2003. 228:111–133.
Article
40. Young JC, Barral JM, Ulrich Hartl F. More than folding: localized functions of cytosolic chaperones. Trends Biochem Sci. 2003. 28:541–547.
Article
41. Chiang HL, Terlecky SR, Plant CP, Dice JF. A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science. 1989. 246:382–385.
Article
42. Bercovich B, Stancovski I, Mayer A, Blumenfeld N, Laszlo A, Schwartz AL, et al. Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70. J Biol Chem. 1997. 272:9002–9010.
Article
43. Mosser DD, Morimoto RI. Molecular chaperones and the stress of oncogenesis. Oncogene. 2004. 23:2907–2918.
Article
44. Yaglom JA, Gabai VL, Sherman MY. High levels of heat shock protein Hsp72 in cancer cells suppress default senescence pathways. Cancer Res. 2007. 67:2373–2381.
Article
45. Gabai VL, Meriin AB, Yaglom JA, Volloch VZ, Sherman MY. Role of Hsp70 in regulation of stress-kinase JNK: implications in apoptosis and aging. FEBS Lett. 1998. 438:1–4.
Article
46. Gabai VL, Budagova KR, Sherman MY. Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents. Oncogene. 2005. 24:3328–3338.
Article
47. Evans CG, Chang L, Gestwicki JE. Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem. 2010. 53:4585–4602.
Article
48. Bottoni P, Giardina B, Scatena R. Proteomic profiling of heat shock proteins: an emerging molecular approach with direct pathophysiological and clinical implications. Proteomics Clin Appl. 2009. 3:636–653.
Article
49. Powers MV, Clarke PA, Workman P. Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer Cell. 2008. 14:250–262.
Article
50. Prodromou C, Pearl LH. Structure and functional relationships of Hsp90. Curr Cancer Drug Targets. 2003. 3:301–323.
Article
51. Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell. 1997. 90:65–75.
Article
52. Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM. The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J Biol Chem. 2000. 275:37181–37186.
Article
53. Söti C, Rácz A, Csermely P. A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket. J Biol Chem. 2002. 277:7066–7075.
Article
54. Garnier C, Lafitte D, Tsvetkov PO, Barbier P, Leclerc-Devin J, Millot JM, et al. Binding of ATP to heat shock protein 90: evidence for an ATP-binding site in the C-terminal domain. J Biol Chem. 2002. 277:12208–12214.
55. Wandinger SK, Richter K, Buchner J. The Hsp90 chaperone machinery. J Biol Chem. 2008. 283:18473–18477.
Article
56. Powers MV, Workman P. Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett. 2007. 581:3758–3769.
Article
57. Isaacs JS, Xu W, Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell. 2003. 3:213–217.
Article
58. Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Höhfeld J, et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol. 2001. 3:93–96.
Article
59. Ciocca DR, Clark GM, Tandon AK, Fuqua SA, Welch WJ, McGuire WL. Heat shock protein hsp70 in patients with axillary lymph node-negative breast cancer: prognostic implications. J Natl Cancer Inst. 1993. 85:570–574.
Article
60. Pandey P, Saleh A, Nakazawa A, Kumar S, Srinivasula SM, Kumar V, et al. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J. 2000. 19:4310–4322.
Article
61. Workman P. Altered states: selectively drugging the Hsp90 cancer chaperone. Trends Mol Med. 2004. 10:47–51.
Article
62. Price JT, Quinn JM, Sims NA, Vieusseux J, Waldeck K, Docherty SE, et al. The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Cancer Res. 2005. 65:4929–4938.
Article
63. Neckers L, Schulte TW, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs. 1999. 17:361–373.
64. Schulte TW, Neckers LM. The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol. 1998. 42:273–279.
Article
65. Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 1995. 36:305–315.
Article
66. Banerji U, O'Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol. 2005. 23:4152–4161.
Article
67. Chiosis G. Discovery and development of purine-scaffold Hsp90 inhibitors. Curr Top Med Chem. 2006. 6:1183–1191.
Article
68. He H, Zatorska D, Kim J, Aguirre J, Llauger L, She Y, et al. Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J Med Chem. 2006. 49:381–390.
Article
69. Chandarlapaty S, Sawai A, Ye Q, Scott A, Silinski M, Huang K, et al. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res. 2008. 14:240–248.
Article
70. Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, et al. NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res. 2008. 10:R33.
Article
71. Wang Y, Trepel JB, Neckers LM, Giaccone G. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs. 2010. 11:1466–1476.
72. Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, et al. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Ther. 2009. 8:921–929.
Article
73. Powers MV, Workman P. Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer. 2006. 13:Suppl 1. S125–S135.
Article
74. Basso AD, Solit DB, Munster PN, Rosen N. Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. Oncogene. 2002. 21:1159–1166.
Article
75. Münster PN, Basso A, Solit D, Norton L, Rosen N. Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. Clin Cancer Res. 2001. 7:2228–2236.
76. Xing H, Weng D, Chen G, Tao W, Zhu T, Yang X, et al. Activation of fibronectin/ PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells. Cancer Lett. 2008. 261:108–119.
Article
77. Kang HJ, Hong MK, Jung SK, Kim LS. The role of heat shock proteins 70/90 as potential molecular therapeutic targets in breast cancer. J Breast Cancer. 2007. 10:231–240.
Article
78. Pick E, Kluger Y, Giltnane JM, Moeder C, Camp RL, Rimm DL, et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 2007. 67:2932–2937.
Article
79. Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res. 2011. 17:5132–5139.
Article
80. Hanson BE, Vesole DH. Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent. Expert Opin Investig Drugs. 2009. 18:1375–1383.
Article
81. Chandarlapaty S, Scaltriti M, Angelini P, Ye Q, Guzman M, Hudis CA, et al. Inhibitors of HSP90 block p95-HER2 signaling in trastuzumab-resistant tumors and suppress their growth. Oncogene. 2010. 29:325–334.
Article
82. Wong C, Chen S. Heat shock protein 90 inhibitors: new mode of therapy to overcome endocrine resistance. Cancer Res. 2009. 69:8670–8677.
Article
83. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci U S A. 2009. 106:8368–8373.
Article
Full Text Links
  • JBC
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr