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Breast Cancer Research
Published in: Breast Cancer Research 4/2010

Open Access 01-08-2010 | Research article

Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule

Authors: Hazem Ghebeh, Cynthia Lehe, Eman Barhoush, Khaldoon Al-Romaih, Asma Tulbah, Monther Al-Alwan, Siti-Faujiah Hendrayani, Pulicat Manogaran, Ayodele Alaiya, Taher Al-Tweigeri, Abdelilah Aboussekhra, Said Dermime

Published in: Breast Cancer Research | Issue 4/2010

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Abstract

Introduction

B7-H1 (PD-L1, CD274) is a T cell inhibitory molecule expressed in many types of cancer, leading to immune escape of tumor cells. Indeed, in previous reports we have shown an association of B7-H1 expression with high-risk breast cancer patients.

Methods

In the current study, we used immunohistochemistry, immunofluorescence and Western blot techniques to investigate the effect of neoadjuvant chemotherapy on the expression of B7-H1 in breast cancer cells.

Results

Among tested chemotherapeutic agents, doxorubicin was the most effective in downregulating cell surface expression of B7-H1 in vitro. These results were validated in vivo in a xenograft mouse model, as well as in murine heart tissue known to constitutively express B7-H1. The doxorubicin-dependent cell surface downregulation of B7-H1 was accompanied by an upregulation of B7-H1 in the nucleus. This re-distribution of B7-H1 was concurrent with a similar translocation of phosphorylated AKT to the nucleus. Inhibition of the PI3K/AKT pathway abrogated the doxorubicin-mediated nuclear up-regulation of B7-H1, suggesting an involvement of PI3K/AKT pathway in the nuclear up-regulation of B7-H1. Interestingly, siRNA knock down of B7-H1 lead to an increase in spontaneous apoptosis, as well as doxorubicin-induced apoptosis, which indicates an anti-apoptotic role for B7-H1 in breast cancer cells. The novel discovery of B7-H1 expression in the nuclei of breast cancer cells suggests that B7-H1 has functions other than inhibition of T cells.

Conclusions

Our findings explain the previously reported immunomodulatory effect of anthracyclines on cancer cells, and provide a link between immunoresistance and chemoresistance. Finally these results suggest the use of dual combinatorial agents to inhibit B7-H1 beside chemotherapy, in breast cancer patients.
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Literature
1.
Weiss RB: The anthracyclines: will we ever find a better doxorubicin?. Semin Oncol. 1992, 19: 670-686.PubMed
2.
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005, 365: 1687-1717. 10.1016/S0140-6736(05)66544-0.
3.
Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M: VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007, 25: 5458-5464. 10.1200/JCO.2007.11.9958.CrossRefPubMed
4.
Ferme C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Divine M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vie B, Kluin-Nelemans JC, Viseu F, Baars JW, et al: Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007, 357: 1916-1927. 10.1056/NEJMoa064601.CrossRefPubMed
5.
Ravindranath Y: Recent advances in pediatric acute lymphoblastic and myeloid leukemia. Curr Opin Oncol. 2003, 15: 23-35. 10.1097/00001622-200301000-00004.CrossRefPubMed
6.
Apetoh L, Mignot G, Panaretakis T, Kroemer G, Zitvogel L: Immunogenicity of anthracyclines: moving towards more personalized medicine. Trends Mol Med. 2008, 14: 141-151. 10.1016/j.molmed.2008.02.002.CrossRefPubMed
7.
Ehrke MJ, Ryoyama K, Cohen SA: Cellular basis for adriamycin-induced augmentation of cell-mediated cytotoxicity in culture. Cancer Res. 1984, 44: 2497-2504.PubMed
8.
Maccubbin DL, Wing KR, Mace KF, Ho RL, Ehrke MJ, Mihich E: Adriamycin-induced modulation of host defenses in tumor-bearing mice. Cancer Res. 1992, 52: 3572-3576.PubMed
9.
Haskill JS: Adriamycin-activated macrophages as tumor growth inhibitors. Cancer Res. 1981, 41: 3852-3856.PubMed
10.
Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007, 13: 54-61. 10.1038/nm1523.CrossRefPubMed
11.
Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L: Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007, 13: 1050-1059. 10.1038/nm1622.CrossRefPubMed
12.
Dermime S, Armstrong A, Hawkins RE, Stern PL: Cancer vaccines and immunotherapy. Br Med Bull. 2002, 62: 149-162. 10.1093/bmb/62.1.149.CrossRefPubMed
13.
Dermime S, Gilham DE, Shaw DM, Davidson EJ, Meziane el-K, Armstrong A, Hawkins RE, Stern PL: Vaccine and antibody-directed T cell tumour immunotherapy. Biochim Biophys Acta. 2004, 1704: 11-35.PubMed
14.
Abbas AK, Sharpe AH: T-cell stimulation: an abundance of B7s. Nat Med. 1999, 5: 1345-1346. 10.1038/70905.CrossRefPubMed
15.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000, 192: 1027-1034. 10.1084/jem.192.7.1027.CrossRefPubMedPubMedCentral
16.
Tamura H, Dong H, Zhu G, Sica GL, Flies DB, Tamada K, Chen L: B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function. Blood. 2001, 97: 1809-1816. 10.1182/blood.V97.6.1809.CrossRefPubMed
17.
Dong H, Zhu G, Tamada K, Chen L: B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999, 5: 1365-1369. 10.1038/70932.CrossRefPubMed
18.
Selenko-Gebauer N, Majdic O, Szekeres A, Hofler G, Guthann E, Korthauer U, Zlabinger G, Steinberger P, Pickl WF, Stockinger H, Knapp W, Stockl J: B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol. 2003, 170: 3637-3644.CrossRefPubMed
19.
Zang X, Allison JP: The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res. 2007, 13: 5271-5279. 10.1158/1078-0432.CCR-07-1030.CrossRefPubMed
20.
Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A, Ajarim D, Al-Tweigeri T, Dermime S: The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006, 8: 190-198. 10.1593/neo.05733.CrossRefPubMedPubMedCentral
21.
Trevisan MG, Poppi RJ: Determination of doxorubicin in human placenta by excitation-emission matrix fluoresence and multi-way analysis. Analytica Chimica Acta. 2003, 493: 69-81. 10.1016/S0003-2670(03)00864-X.CrossRef
22.
Bell DH: Characterization of the fluorescence of the antitumor agent, mitoxantrone. Biochim Biophys Acta. 1988, 949: 132-137.CrossRefPubMed
23.
Wang W, Furneaux H, Cheng H, Caldwell MC, Hutter D, Liu Y, Holbrook N, Gorospe M: HuR regulates p21 mRNA stabilization by UV light. Mol Cell Biol. 2000, 20: 760-769. 10.1128/MCB.20.3.760-769.2000.CrossRefPubMedPubMedCentral
24.
Al-Mohanna MA, Al-Khalaf HH, Al-Yousef N, Aboussekhra A: The p16INK4a tumor suppressor controls p21WAF1 induction in response to ultraviolet light. Nucleic Acids Res. 2007, 35: 223-233. 10.1093/nar/gkl1075.CrossRefPubMed
25.
Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S: FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy. BMC Cancer. 2008, 8: 57-10.1186/1471-2407-8-57.CrossRefPubMedPubMedCentral
26.
Al-Tweigeri T, Ajarim D, Alsayed A, Rahal M, Alshabanah M, Tulbah A, Al-Malik O, Fatani D, El-Husseiny G, Elkum N, Ezzat A: Prospective phase II study of neoadjuvant Doxorubicin followed by cisplatin/docetaxel in locally advanced breast cancer. Medical Oncology. 2009.
27.
Ghebeh H, Tulbah A, Mohammed S, Elkum N, Bin Amer SM, Al-Tweigeri T, Dermime S: Expression of B7-H1 in breast cancer patients is strongly associated with high proliferative Ki-67-expressing tumor cells. Int J Cancer. 2007, 121: 751-758. 10.1002/ijc.22703.CrossRefPubMed
28.
Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR: Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995, 182: 1545-1556. 10.1084/jem.182.5.1545.CrossRefPubMed
29.
Crane CA, Panner A, Murray JC, Wilson SP, Xu H, Chen L, Simko JP, Waldman FM, Pieper RO, Parsa AT: PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene. 2009, 28: 306-312. 10.1038/onc.2008.384.CrossRefPubMed
30.
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO: Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007, 13: 84-88. 10.1038/nm1517.CrossRefPubMed
31.
Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L: B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008, 111: 3635-3643. 10.1182/blood-2007-11-123141.CrossRefPubMedPubMedCentral
32.
Kim YS, Park GB, Lee H-K, Song H, Choi I-H, Lee WJ, Hur DY: Cross-linking of B7-H1 on EBV-transformed B cells induces apoptosis through reactive oxygen species production, JNK signaling activation, and fasL expression. J Immunol. 2008, 181: 6158-6169.CrossRefPubMed
33.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L: Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002, 8: 793-800.CrossRefPubMed
34.
Gewirtz DA: A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999, 57: 727-741. 10.1016/S0006-2952(98)00307-4.CrossRefPubMed
35.
Schwartz HS, Grindey GB: Adriamycin and daunorubicin: a comparison of antitumor activities and tissue uptake in mice following immunosuppression. Cancer Res. 1973, 33: 1837-1844.PubMed
36.
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L: Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004, 56: 185-229. 10.1124/pr.56.2.6.CrossRefPubMed
37.
Vereecque R, Saudemont A, Quesnel B: Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells. Leukemia. 2004, 18: 1223-1230. 10.1038/sj.leu.2403391.CrossRefPubMed
38.
Mokyr MB, Kalinichenko TV, Gorelik L, Bluestone JA: Importance of the B7-2 molecule for low dose melphalan-induced acquisition of tumor-eradicating immunity by mice bearing a large MOPC-315 tumor. J Immunol. 1998, 160: 1866-1874.PubMed
39.
Zhang P, Su DM, Liang M, Fu J: Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol. 2008, 45: 1470-1476. 10.1016/j.molimm.2007.08.013.CrossRefPubMed
40.
Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, Coutant F, Metivier D, Pichard E, Aucouturier P, Pierron G, Garrido C, Zitvogel L, Kroemer G: Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005, 202: 1691-1701. 10.1084/jem.20050915.CrossRefPubMedPubMedCentral
41.
42.
Clark AS, West K, Streicher S, Dennis PA: Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 2002, 1: 707-717.PubMed
43.
Li X, Lu Y, Liang K, Liu B, Fan Z: Differential responses to doxorubicin-induced phosphorylation and activation of Akt in human breast cancer cells. Breast Cancer Res. 2005, 7: R589-597. 10.1186/bcr1259.CrossRefPubMedPubMedCentral
44.
Fujiwara Y, Kawada K, Takano D, Tanimura S, Ozaki K, Kohno M: Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner. Biochem Biophys Res Commun. 2006, 340: 560-566. 10.1016/j.bbrc.2005.12.039.CrossRefPubMed
45.
Davies SP, Reddy H, Caivano M, Cohen P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000, 351: 95-105. 10.1042/0264-6021:3510095.CrossRefPubMedPubMedCentral
46.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005, 307: 1098-1101. 10.1126/science.1106148.CrossRefPubMed
47.
Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991, 266: 1672-1677. 10.1001/jama.266.12.1672.CrossRefPubMed
Metadata
Title
Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule
Authors
Hazem Ghebeh
Cynthia Lehe
Eman Barhoush
Khaldoon Al-Romaih
Asma Tulbah
Monther Al-Alwan
Siti-Faujiah Hendrayani
Pulicat Manogaran
Ayodele Alaiya
Taher Al-Tweigeri
Abdelilah Aboussekhra
Said Dermime
Publication date
01-08-2010
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 4/2010
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2605

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