Top

Published in:

01-06-2013 | Review Article

The significance of heat shock proteins in breast cancer therapy

Authors: Sevil Oskay Halacli, Burcin Halacli, Kadri Altundag

Published in: Medical Oncology | Issue 2/2013

Abstract

The evalutionary conserved heat shock proteins are involved basically life protecting mechanisms against harmful extracellular effects such as primarily heat shock response. Normally, the expression of these proteins is increased for cellular adaptation to high temperature. This increase is also important in the etiology of breast cancer. Overexpression of heat shock proteins is associated with reduced disease-free survival in breast cancer. However, increased expression of these proteins is related to acquired resistance of traditional chemotherapeutic drugs in use in breast cancer treatment. In this review, we discuss the multiple roles of heatshock proteins in resistance and where we are to overcome this in clinical practice.

Ciocca DR, Calderwood SK. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 2005;10:86–103.PubMedCrossRef

Georgopoulos C, Welch WJ. Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol. 1993;9:601–34.PubMedCrossRef

Hightower LE. Heat shock, stress proteins, chaperones, and proteotoxicity. Cell. 1991;66:191–7.PubMedCrossRef

Gething MJ, Sambrook J. Protein folding in the cell. Nature. 1992;355:33–45.PubMedCrossRef

Netzer WJ, Hartl FU. Protein folding in the cytosol: chaperonin-dependent and -independent mechanisms. Trends Biochem Sci. 1998;23:68–73.PubMedCrossRef

Freeman BC, Yamamoto KR. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science. 2002;296:2232–5.PubMedCrossRef

Queitsch C, Sangster TA, Lindquist S. Hsp90 as a capacitor of phenotypic variation. Nature. 2002;417:618–24.PubMedCrossRef

Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005;5:761–72.PubMedCrossRef

O’Neill PA, et al. Increased risk of malignant progression in benign proliferating breast lesions defined by expression of heat shock protein 27. Br J Cancer. 2004;90:182–8.PubMedCrossRef

10.

Kim LS, Kim JH. Heat shock protein as molecular targets for breast cancer therapeutics. J Breast Cancer. 2011;14:167–74.PubMedCrossRef

11.

Kang SH, et al. Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability. BMC Cancer. 2008;8:286.PubMedCrossRef

12.

Hansen RK, et al. Hsp27 overexpression inhibits doxorubicin-induced apoptosis in human breast cancer cells. Breast Cancer Res Treat. 1999;56:187–96.PubMedCrossRef

13.

Oesterreich S, et al. The small heat shock protein hsp27 is correlated with growth and drug resistance in human breast cancer cell lines. Cancer Res. 1993;53:4443–8.PubMed

14.

Wei L, et al. Hsp27 participates in the maintenance of breast cancer stem cells through regulation of epithelial-mesenchymal transition and nuclear factor-kappaB. Breast Cancer Res. 2011;13:R101.PubMedCrossRef

15.

Shin KD, et al. Blocking tumor cell migration and invasion with biphenyl isoxazole derivative KRIBB3, a synthetic molecule that inhibits Hsp27 phosphorylation. J Biol Chem. 2005;280:41439–48.PubMedCrossRef

16.

Cayado-Gutierrez N, et al. Downregulation of Hsp27 (HSPB1) in MCF-7 human breast cancer cells induces upregulation of PTEN. Cell Stress Chaperones. 2013;18:243–9.PubMedCrossRef

17.

Straume O, et al. Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer. Proc Natl Acad Sci USA. 2012;109:8699–704.PubMedCrossRef

18.

Sarkar R, et al. Sulphoraphane, a naturally occurring isothiocyanate induces apoptosis in breast cancer cells by targeting heat shock proteins. Biochem Biophys Res Commun. 2012;427:80–5.PubMedCrossRef

19.

Sims JT, et al. Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-kappaB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS ONE. 2013;8:e55509.PubMedCrossRef

20.

Antoon JW, et al. Pharmacology and anti-tumor activity of RWJ67657, a novel inhibitor of p38 mitogen activated protein kinase. Am J Cancer Res. 2012;2:446–58.PubMed

21.

Lee CH, et al. Inhibition of heat shock protein (Hsp) 27 potentiates the suppressive effect of Hsp90 inhibitors in targeting breast cancer stem-like cells. Biochimie. 2012;94:1382–9.PubMedCrossRef

22.

Vargas-Roig LM, et al. Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy. Int J Cancer. 1998;79:468–75.PubMedCrossRef

23.

Ciocca DR, et al. Heat shock protein hsp70 in patients with axillary lymph node-negative breast cancer: prognostic implications. J Natl Cancer Inst. 1993;85:570–4.PubMedCrossRef

24.

Hansen RK, et al. Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells. Biochem Biophys Res Commun. 1997;239:851–6.PubMedCrossRef

25.

Nylandsted J, et al. Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci USA. 2000;97:7871–6.PubMedCrossRef

26.

Nylandsted J, Brand K, Jaattela M. Heat shock protein 70 is required for the survival of cancer cells. Ann N Y Acad Sci. 2000;926:122–5.PubMedCrossRef

27.

Barnes JA, et al. Expression of inducible Hsp70 enhances the proliferation of MCF-7 breast cancer cells and protects against the cytotoxic effects of hyperthermia. Cell Stress Chaperones. 2001;6:316–25.PubMedCrossRef

28.

Kalogeraki A, et al. Correlation of heat shock protein (HSP70) expression with cell proliferation (MIB1), estrogen receptors (ER) and clinicopathological variables in invasive ductal breast carcinomas. J Exp Clin Cancer Res. 2007;26:367–8.PubMed

29.

Davidoff AM, Iglehart JD, Marks JR. Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancers. Proc Natl Acad Sci USA. 1992;89:3439–42.PubMedCrossRef

30.

Sims JD, McCready J, Jay DG. Extracellular heat shock protein (Hsp)70 and Hsp90alpha assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS ONE. 2011;6:e18848.PubMedCrossRef

31.

Chen CH, et al. Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res. 2000;60:1035–42.PubMed

32.

Kim JH, et al. Enhanced immunity by NeuEDhsp70 DNA vaccine Is needed to combat an aggressive spontaneous metastatic breast cancer. Mol Ther. 2005;11:941–9.PubMedCrossRef

33.

Hauser H, et al. Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines. Gene Ther. 2004;11:924–32.PubMedCrossRef

34.

Pakravan N, Soudi S, Hassan ZM. N-terminally fusion of Her2/neu to HSP70 decreases efficiency of Her2/neu DNA vaccine. Cell Stress Chaperones. 2010;15:631–8.PubMedCrossRef

35.

Cheng Q, et al. Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. Breast Cancer Res. 2012;14:R62.PubMedCrossRef

36.

Pick E, et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 2007;67:2932–7.PubMedCrossRef

37.

Yano M, et al. Expression and roles of heat shock proteins in human breast cancer. Jpn J Cancer Res. 1996;87:908–15.PubMedCrossRef

38.

Giordano C, et al. Leptin increases HER2 protein levels through a STAT3-mediated up-regulation of Hsp90 in breast cancer cells. Mol Oncol. 2012;7891:123–8.

39.

El Hamidieh A, Grammatikakis N, Patsavoudi E. Cell surface Cdc37 participates in extracellular HSP90 mediated cancer cell invasion. PLoS ONE. 2012;7:e42722.PubMedCrossRef

40.

Yano M, et al. Expression of hsp90 and cyclin D1 in human breast cancer. Cancer Lett. 1999;137:45–51.PubMedCrossRef

41.

Kang SA, et al. Hsp90 rescues PTK6 from proteasomal degradation in breast cancer cells. Biochem J. 2012;447:313–20.PubMedCrossRef

42.

Zuo K, et al. Short-hairpin RNA-mediated Heat shock protein 90 gene silencing inhibits human breast cancer cell growth in vitro and in vivo. Biochem Biophys Res Commun. 2012;421:396–402.PubMedCrossRef

43.

Cooper LC, et al. Hsp90alpha/beta associates with the GSK3beta/axin1/phospho-beta-catenin complex in the human MCF-7 epithelial breast cancer model. Biochem Biophys Res Commun. 2011;413:550–4.PubMedCrossRef

44.

DeBoer C, et al. Geldanamycin, a new antibiotic. J Antibiot (Tokyo). 1970;23:442–7.CrossRef

45.

Prodromou C, et al. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell. 1997;90:65–75.PubMedCrossRef

46.

Taldone T, et al. Design, synthesis, and evaluation of small molecule Hsp90 probes. Bioorg Med Chem. 2011;19:2603–14.PubMedCrossRef

47.

Wang K, et al. Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/beta-catenin signaling in HER2 overexpressing human breast cancer cells. Oncol Rep. 2007;17:89–96.PubMed

48.

Pedersen NM, et al. Geldanamycin-induced down-regulation of ErbB2 from the plasma membrane is clathrin dependent but proteasomal activity independent. Mol Cancer Res. 2008;6:491–500.PubMedCrossRef

49.

Mandler R, et al. Immunoconjugates of geldanamycin and anti-HER2 monoclonal antibodies: antiproliferative activity on human breast carcinoma cell lines. J Natl Cancer Inst. 2000;92:1573–81.PubMedCrossRef

50.

Supko JG, et al. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 1995;36:305–15.PubMedCrossRef

51.

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;42:273–9.PubMedCrossRef

52.

Schulz R, et al. Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression. J Exp Med. 2012;209:275–89.PubMedCrossRef

53.

Schulz R, Dobbelstein M, Moll UM. HSP90 inhibitor antagonizing MIF: the specifics of pleiotropic cancer drug candidates. Oncoimmunology. 2012;1:1425–6.PubMedCrossRef

54.

Rodrigues LM, et al. Effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on NEU/HER2 overexpressing mammary tumours in MMTV-NEU-NT mice monitored by Magnetic Resonance Spectroscopy. BMC Res Notes. 2012;5:250.PubMedCrossRef

55.

Modi S, 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;17:5132–9.PubMedCrossRef

56.

Gartner EM, et al. A phase II study of 17-allylamino-17-demethoxygeldanamycin in metastatic or locally advanced, unresectable breast cancer. Breast Cancer Res Treat. 2012;131:933–7.PubMedCrossRef

57.

Nowakowski GS, et al. A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clin Cancer Res. 2006;12(20 Pt 1):6087–93.PubMedCrossRef

58.

Wong C, et al. AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies. Breast Cancer Res Treat. 2012;134:671–81.PubMedCrossRef

59.

Jhaveri K, et al. A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors. Clin Cancer Res. 2012;18:5090–8.PubMedCrossRef

60.

Aregbe AO, et al. Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors. Cancer Chemother Pharmacol. 2012;70:201–5.PubMedCrossRef

61.

Jego G et al. Targeting heat shock proteins in cancer. 2010 Nov 13. [Epub ahead of print].

Title: The significance of heat shock proteins in breast cancer therapy
Authors: Sevil Oskay Halacli
Burcin Halacli
Kadri Altundag
Publication date: 01-06-2013
Publisher: Springer US
Published in: Medical Oncology / Issue 2/2013
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-013-0575-y

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The significance of heat shock proteins in breast cancer therapy

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2013

Successful large-volume cerebrospinal fluid aspiration for an accidental overdose of intrathecal cytarabine

Identification and validation that up-expression of HOXA13 is a novel independent prognostic marker of a worse outcome in gastric cancer based on immunohistochemistry

Sox2 expression predicts poor survival of hepatocellular carcinoma patients and it promotes liver cancer cell invasion by activating Slug

Inverse correlation between Naa10p and MMP-9 expression and the combined prognostic value in breast cancer patients

Diagnostic and prognostic significance of CA IX and suPAR in gastric cancer

TL-118—anti-angiogenic treatment in pancreatic cancer: a case report

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page