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ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer

ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer
ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer
Purpose: Members of the Bcl-2 family act as master regulators of mitochondrial homeostasis and apoptosis. We analyzed whether ERBB2 influences the prognosis of breast cancer by influencing the proapoptotic versus antiapoptotic balance of Bcl-2 family members. Experimental Design: ERBB2-regulated Bcl-2 family members were identified by inducible expression of ERBB2 in MCF-7 breast cancer cells and by correlation analysis with ERBB2 expression in breast carcinomas. The prognostic relevance of ERBB2-regulated and all additional Bcl-2 family members was determined in 782 patients with untreated node-negative breast cancer. The biological relevance of ERBB2-induced inhibition of apoptosis was validated in a murine tumor model allowing conditional ERBB2 expression. Results: ERBB2 caused an antiapoptotic phenotype by upregulation of MCL-1, TEGT, BAG1, BNIP1, and BECN1 as well as downregulation of BAX, BMF, BNIPL, CLU, and BCL2L13. Upregulation of the antiapoptotic MCL-1 [P = 0.001, hazard ratio (HR) 1.5] and BNIP3 (P = 0.024; HR, 1.4) was associated with worse prognosis considering metastasis-free interval, whereas clusterin (P = 0.008; HR, 0.88) and the proapoptotic BCL2L13 (P = 0.019; HR, 0.45) were associated with better prognosis. This indicates that ERBB2 alters the expression of Bcl-2 family members in a way that leads to adverse prognosis. Analysis of apoptosis and tumor remission in a murine tumor model confirmed that the prototypic Bcl-2 family member Bcl-xL could partially substitute for ERBB2 to antagonize tumor remission. Conclusions: Our results support the concept that ERBB2 influences the expression of Bcl-2 family members to induce an antiapoptotic phenotype. Antagonization of antiapoptotic Bcl-2 family members might improve breast cancer therapy, whereby MCL-1 and BNIP3 represent promising targets. Clin Cancer Res; 16(2); 451-60. (C)2010 AACR.
mouse-tumor model, cell lung-cancer, in-situ drug-resistance, mammalian-cells, Bcl-2 family members, breast cancer, ERBB2
1078-0432
451-460
Petry, I.B.
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Fieber, E.
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Schmidt, M.
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Gehrmann, M.
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Gebhard, S.
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Hermes, M.
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Schormann, W.
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Selinski, S.
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Freis, E.
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Schwender, H.
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Brulport, M.
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Ickstadt, K.
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Rahnenfuhrer, J.
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Maccoux, L.
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West, J.
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Kolbl, H.
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Schuler, M.
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Hengstler, J.G.
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Petry, I.B.
ab4648ab-ae55-499c-a9a9-8eb480a14219
Fieber, E.
bd482fc0-56d5-4910-9a9e-06de7d41fa22
Schmidt, M.
68f4851a-9b14-48a9-b08f-854618465310
Gehrmann, M.
a1f9e386-a460-411a-89ae-6470b901d9f6
Gebhard, S.
a85fca49-5a90-4ba9-8fa0-150d77d8d472
Hermes, M.
ebab427d-1a57-41b0-91f9-999ada711665
Schormann, W.
409dc23a-c2e4-4375-b374-547073f91eec
Selinski, S.
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Freis, E.
9d8016b0-7dc7-4c5c-a8fa-965d2726f8d7
Schwender, H.
237c15a0-cdce-4f63-90bc-525518d8ce5d
Brulport, M.
fc618c1b-b329-4f73-822a-431e62ae1371
Ickstadt, K.
9f85087c-c5d6-4e89-8e1d-9fb944a3893c
Rahnenfuhrer, J.
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Maccoux, L.
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West, J.
f1c2e060-16c3-44c0-af70-242a1c58b968
Kolbl, H.
2add909a-8e77-4de0-ab58-72f120e278c5
Schuler, M.
f8122754-8127-4c28-95a3-84422a33f7e5
Hengstler, J.G.
ae4a2b59-c041-4fca-9a66-d0d6a7053371

Petry, I.B., Fieber, E., Schmidt, M., Gehrmann, M., Gebhard, S., Hermes, M., Schormann, W., Selinski, S., Freis, E., Schwender, H., Brulport, M., Ickstadt, K., Rahnenfuhrer, J., Maccoux, L., West, J., Kolbl, H., Schuler, M. and Hengstler, J.G. (2010) ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer. Clinical Cancer Research, 16 (2), 451-460. (doi:10.1158/1078-0432.CCR-09-1617). (PMID:20068093)

Record type: Article

Abstract

Purpose: Members of the Bcl-2 family act as master regulators of mitochondrial homeostasis and apoptosis. We analyzed whether ERBB2 influences the prognosis of breast cancer by influencing the proapoptotic versus antiapoptotic balance of Bcl-2 family members. Experimental Design: ERBB2-regulated Bcl-2 family members were identified by inducible expression of ERBB2 in MCF-7 breast cancer cells and by correlation analysis with ERBB2 expression in breast carcinomas. The prognostic relevance of ERBB2-regulated and all additional Bcl-2 family members was determined in 782 patients with untreated node-negative breast cancer. The biological relevance of ERBB2-induced inhibition of apoptosis was validated in a murine tumor model allowing conditional ERBB2 expression. Results: ERBB2 caused an antiapoptotic phenotype by upregulation of MCL-1, TEGT, BAG1, BNIP1, and BECN1 as well as downregulation of BAX, BMF, BNIPL, CLU, and BCL2L13. Upregulation of the antiapoptotic MCL-1 [P = 0.001, hazard ratio (HR) 1.5] and BNIP3 (P = 0.024; HR, 1.4) was associated with worse prognosis considering metastasis-free interval, whereas clusterin (P = 0.008; HR, 0.88) and the proapoptotic BCL2L13 (P = 0.019; HR, 0.45) were associated with better prognosis. This indicates that ERBB2 alters the expression of Bcl-2 family members in a way that leads to adverse prognosis. Analysis of apoptosis and tumor remission in a murine tumor model confirmed that the prototypic Bcl-2 family member Bcl-xL could partially substitute for ERBB2 to antagonize tumor remission. Conclusions: Our results support the concept that ERBB2 influences the expression of Bcl-2 family members to induce an antiapoptotic phenotype. Antagonization of antiapoptotic Bcl-2 family members might improve breast cancer therapy, whereby MCL-1 and BNIP3 represent promising targets. Clin Cancer Res; 16(2); 451-60. (C)2010 AACR.

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e-pub ahead of print date: 12 January 2010
Published date: 15 January 2010
Additional Information: ISI Document Delivery No: 607ZE Times Cited: 14 Cited Reference Count: 44 Petry, Ilka Brigitte Fieber, Esther Schmidt, Marcus Gehrmann, Mathias Gebhard, Susanne Hermes, Matthias Schormann, Wiebke Selinski, Silvia Freis, Evgenia Schwender, Holger Brulport, Marc Ickstadt, Katja Rahnenfuehrer, Joerg Maccoux, Lindsey West, Jonathan Koelbl, Heinz Schuler, Martin Hengstler, Jan Georg Stiftung Rheinland Pfalz for Innovation [646]; NGFN-BMBF Stiftung Rheinland Pfalz for Innovation (Project 646) and by the NGFN-BMBF project OncoProfile. Amer assoc cancer research Philadelphia
Keywords: mouse-tumor model, cell lung-cancer, in-situ drug-resistance, mammalian-cells, Bcl-2 family members, breast cancer, ERBB2
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 346445
URI: http://eprints.soton.ac.uk/id/eprint/346445
ISSN: 1078-0432
PURE UUID: 713cb9d7-2bef-4c36-a8f2-6e21fa0492d6
ORCID for J. West: ORCID iD orcid.org/0000-0002-5709-6790

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Date deposited: 20 Dec 2012 11:33
Last modified: 15 Mar 2024 03:43

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Contributors

Author: I.B. Petry
Author: E. Fieber
Author: M. Schmidt
Author: M. Gehrmann
Author: S. Gebhard
Author: M. Hermes
Author: W. Schormann
Author: S. Selinski
Author: E. Freis
Author: H. Schwender
Author: M. Brulport
Author: K. Ickstadt
Author: J. Rahnenfuhrer
Author: L. Maccoux
Author: J. West ORCID iD
Author: H. Kolbl
Author: M. Schuler
Author: J.G. Hengstler

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