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Hsp27 overexpression inhibits doxorubicin–induced apoptosis in human breast cancer cells

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Abstract

Previously we demonstrated that heat shock protein 27 (hsp27) overexpression confers resistance to the chemotherapeutic agent doxorubicin in MDA–MB–231 breast cancer cells. Since induction of apoptosis is one underlying mechanism of chemotherapeutic drug action, we investigated the effect of hsp27 overexpression on doxorubicin–induced apoptosis, finding that hsp27 protects MDA–MB–231 cells from apoptosis. We also examined expression of the doxorubicin target, topoisomerase II (topo II), in control and hsp27–overexpressing stable transfectants, as topo II expression is important for both drug sensitivity and the initiation of apoptosis by doxorubicin. The relative levels of both topo IIα and β were higher in the controls than the hsp27–overexpressing clones, suggesting that the apoptotic protective effect of hsp27 overexpression in MDA–MB–231 cells is associated with altered topo II expression.abstract

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References

  1. Hannun YA: Apoptosis and the dilemma of cancer chemotherapy. Blood 89: 1845–1853, 1997

    Google Scholar 

  2. Harris AL, Hockhauser D: Mechanisms of multidrug resistance in cancer treatment. Acta Oncol 31: 205–213, 1992

    Google Scholar 

  3. Robert J, Larsen AK: Drug resistance to topoisomerase II inhibitors. Biochimie 80: 247–254, 1998

    Google Scholar 

  4. Lowe SW, Ruley HE, Jacks T, Housman DE: p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957–967, 1993

    Google Scholar 

  5. Kamesaki S, Kamesaki H, Jorgensen TJ, Tanizawa A, Pommier Y, Cossman J: Bcl-2 protein inhibits etoposide-induced apoptosis through its effects on events subsequent to topoisomerase Il-induced strand breaks and their repair. Cancer Res 53: 4251–4256, 1993

    Google Scholar 

  6. Ciocca RD, Fuqua SAW, Lock-Lim S, Toft DO, Welch WJ, McGuire WL: Response of human breast cancer cells to heat shock and chemotherapeutic drugs. Cancer Res 52: 2648–3654, 1992

    Google Scholar 

  7. Oesterreich S, Weng C-N, Qiu M, Hilsenbeck SG, Osborne CK, Fuqua SAW: The small heat shock protein hsp27 is correlated with growth and drug resistance in human breast cancer cell lines. Cancer Res 53: 4443–4448, 1993

    Google Scholar 

  8. Huot J, Roy G, Lambert H, Chretien P, Landry J: Increased survival after treatments with anticancer agents of Chinese hamster cells expressing the human Mr 27 000 heat shock protein. Cancer Res 51: 5245–5252, 1991

    Google Scholar 

  9. Walker PR, Smitch C, Youdale T, Leblanc J, Whitfield JF, Sikorska M: Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res 51: 1078–1985, 1991

    Google Scholar 

  10. Lemieux P, Oesterreich S, Lawrence JA, Steeg PS, Hilsenbeck SG, Harvey JM, Fuqua SAW: The small heat shock protein hsp27 increases invasiveness but decreases motility of breast cancer cells. Invasion Metastasis 17: 113–123, 1998

    Google Scholar 

  11. Hilsenbeck SG, Friedrichs WG, Schiff R, O'Connell P, Hansen RK, Osborne CK, Fuqua SAW: Statistical analysis of microarray expression data as applied to the problem of tamoxifen resistance. J Natl Cancer Inst 91: 1998

  12. Krishan A: Rapid DNA content analysis by the propidium iodide-hypotonic citrate method. Meth Cell Biol 33: 121–125, 1990

    Google Scholar 

  13. Strasser A, Huang DC, Vaux DL: The role of the bcl-2/ced-9 gene family in cancer and general implications of defects in cell death control for tumourigenesis and resistance to chemotherapy. Biochim Biophys Acta 1333: F151–F178, 1997

    Google Scholar 

  14. Mehlen P, Schulze-Osthoff K, Arrigo AP: Small stress proteins as novel regulators of apoptosis. J Biol Chem 271: 16510–16514, 1996

    Google Scholar 

  15. Mehlen P, Mehlen A, Godet J, Arrigo AP: Hsp27 as a switch between differentiation and apoptosis in murine embryonic stem cells. J Biol Chem 272: 31657–31665, 1997

    Google Scholar 

  16. Oesterreich S, Hilsenbeck S, Ciocca DR, Allred CD, Clark GC, Chamness GC, Osborne CK, Fuqua SAW: The small heat shock protein hsp27 is not an independent prognostic marker in axillary lymph node-negative breast cancer patients. Clin Cancer Res 2: 1199–1206, 1996

    Google Scholar 

  17. Wang H, Jiang Z, Wong YW, Dalton WS, Futscher BW, Chan VTW: Decreased CP-1 (NF-Y) activity results in transcriptional down-regulation of topoisomerase IIa in a doxorubicinresistant variant of human multiple myeloma RPMI 8226. Biochem Biophys Res Commun 231: 217–224, 1997

    Google Scholar 

  18. McPherson JP, Deffie AM, Jones NR, Brown GA, Deuchars KL, Goldenberg GJ: Selective sensitization of adriamycinresistant P388 murine leukemia cells to antineoplastic agents following transfection with human DNA topoisomerase IIa. Anticancer Res 17: 4243–4252, 1997

    Google Scholar 

  19. Smith K, Houlbrook S, Greenall M, Carmichael J, Harris AL: Topoisomerase IIa co-amplification with erbB-2 in human 196 RK Hansen et al. primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitozantrone sensitivity. Oncogene 8: 933–938, 1993

    Google Scholar 

  20. Kim R, Hirabayashi N, Nishiyama M, Saeki S, Toge T, Okada K: Expression of MDRI, GSTπ and topoisomerase II as an indicator of clinical response to adriamycin. Anticancer Res 11: 429–432, 1991

    Google Scholar 

  21. Sandri MI, Hockhauser D, Ayton P, Camplejohn RC, Whitehouse R, Turley H, Gatter K, Hickson ID, Harris AL: Differential expression of the topoisomerase IIa and b genes in human breast cancers. Br J Cancer 73: 1518–1524, 1996

    Google Scholar 

  22. Garrido C, Mehlen P, Fromentin A, Hammann A, Assem M, Arrigo AP, Chauffert B: Inconstant association between 27-kDa heat-shock protein (Hsp27) content and doxorubicin resistance in human colon cancer cells. Eur J Biochem 237: 653–659, 1996

    Google Scholar 

  23. Hashimoto S, Jing Y, Kawazoe N, Masuda Y, Nakajo S, Yoshida T, Kuroiwa Y, Nakaya K: Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs. Leuk Res 21: 875–883, 1997

    Google Scholar 

  24. Bartek J, Iggo R, Gannon J, Lane DP: Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene 5: 893–899, 1990

    Google Scholar 

  25. Guenal I, Fraisse CS, Gaumer S, Mignotte B: Bcl-2 and hsp27 act at different levels to suppress programmed cell death. Oncogene 15: 347–360, 1997

    Google Scholar 

  26. Mehlen P, Preville X, Chareyron P, Briolay J, Klemenz R, Arrigo AP: Constitutive expression of human hsp27, Drosophila hsp27, or human ab-crystallin confers resistance to TNFand oxidative stress-induced cytotoxicity in stably transfected murine L929 fibroblasts. J Immunol 154: 363–374, 1995

    Google Scholar 

  27. Mueller H, Flury N, Liu R, Scheidegger S, Eppenberger U: Tumour necrosis factor and interferon are selectively cytostatic in vitro for hormone-dependent and hormone-independent human breast cancer cells. Eur J Cancer 23A: 2312–2318, 1996

    Google Scholar 

  28. Keane MM, Ettenberg SA, Lowrey GA, Russell EK, Lipkowitz S: Fas expression and function in normal and malignant breast cell lines. Cancer Res 56: 4791–4798, 1996

    Google Scholar 

  29. Jacobson MD: Reactive oxygen species and programmed cell death. Trends Biochem Sci 21: 83–86, 1996

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Oncology, The University of Texas Health Science Center, San Antonio, USA

    Rhonda K. Hansen, Irma Parra, Steffi Oesterreich, Susan G. Hilsenbeck & Suzanne A. W. Fuqua

  2. Angiotech Pharmaceuticals Inc., Vancouver, BC, Canada

    Pierre Lemieux

Authors
  1. Rhonda K. Hansen
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  2. Irma Parra
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  3. Pierre Lemieux
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  4. Steffi Oesterreich
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  5. Susan G. Hilsenbeck
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  6. Suzanne A. W. Fuqua
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Hansen, R.K., Parra, I., Lemieux, P. et al. Hsp27 overexpression inhibits doxorubicin–induced apoptosis in human breast cancer cells. Breast Cancer Res Treat 56, 185–194 (1999). https://doi.org/10.1023/A:1006207009260

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