help button home button Am J Pathol International Conference on Pathology of Chest Diseases
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Järvinen, T. A. H.
Right arrow Articles by Isola, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Järvinen, T. A. H.
Right arrow Articles by Isola, J.
(American Journal of Pathology. 2000;156:839-847.)
© 2000 American Society for Investigative Pathology

Regular Articles

Amplification and Deletion of Topoisomerase II{alpha} Associate with ErbB-2 Amplification and Affect Sensitivity to Topoisomerase II Inhibitor Doxorubicin in Breast Cancer

Tero A. H. Järvinen*, Minna Tanner*{dagger}§, Virpi Rantanen{ddagger}, Maarit Bärlund*, Åke Borg§, Seija Grénman{ddagger} and Jorma Isola*§

From the Laboratory of Cancer Biology,*
University and University Hospital of Tampere, and the Department of Oncology,{dagger}
Tampere University Hospital, Tampere, Finland; the Departments of Medical Biochemistry and Gyneacology and Obstetrics,{ddagger}
University and University Hospital of Turku, Turku, Finland; and the Department of Oncology,§
University of Lund, Lund, Sweden

Topoisomerase II{alpha} (topoII{alpha}) is a key enzyme in DNA replication and a molecular target for many anti-cancer drugs called topoII inhibitors. The topoII{alpha} gene is located at chromosome band 17q12-q21, close to the ErbB-2 oncogene (HER-2/neu), which is the most commonly amplified oncogene in breast cancer. Because of the physical proximity to ErbB-2, copy number aberrations may also occur in the topoII{alpha} gene. These topoII{alpha} gene copy number aberrations may be related to the altered chemosensitivity to topoII inhibitors that breast cancers with ErbB-2 amplification are known to have. We used fluorescence in situ hybridization to study copy number aberrations of both topoII{alpha} and ErbB-2 in nine breast cancer cell lines and in 97 clinical breast tumors, which were selected for the study according to their ErbB-2 status by Southern blotting. TopoII{alpha}-protein expression was studied with Western blot and sensitivity to doxorubicin (a topoII inhibitor) with a 96-well clonogenic in vitro assay. Two of the five cell lines with ErbB-2 gene amplification (SK-BR-3 and UACC-812) showed amplification of topoII{alpha}. In MDA-361 cells, ErbB-2 amplification (14 copies/cell) was associated with a physical deletion of topoII{alpha} (four copies of chromosome 17 centromere and two copies of topoII{alpha}). The topoII{alpha} amplification in UACC-812 cells was associated with 5.9-fold-increased topoII{alpha} protein expression and 2.5-fold-increased sensitivity to the topoII inhibitor, doxorubicin, whereas the deletion in MDA-361 leads to decreased protein expression (45% of control) and a 2.4-fold-increased chemoresistance in vitro. Of 57 ErbB-2-amplified primary breast carcinomas, 25 (44%) showed ErbB-2-topoII{alpha} coamplification and 24 (42%) showed a physical deletion of the topoII{alpha} gene. No topoII{alpha} copy number aberrations were found in 40 primary tumors without ErbB-2 amplification. TopoII{alpha} gene amplification and deletion are common in ErbB-2-amplified breast cancer and are associated with increased or decreased sensitivity to topoII inhibitors in vitro, respectively. These findings may explain the altered chemosensitivity to topoII inhibitors reported in ErbB-2-amplified breast cancers.




This article has been cited by other articles:


Home page
 J. Histochem. Cytochem.Home page
M. Campos, C. Prior, F. Warleta, I. Zudaire, J. Ruiz-Mora, R. Catena, A. Calvo, and J. J. Gaforio
Phenotypic and Genetic Characterization of Circulating Tumor Cells by Combining Immunomagnetic Selection and FICTION Techniques
J. Histochem. Cytochem., July 1, 2008; 56(7): 667 - 675.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
A. Gennari, M. P. Sormani, P. Pronzato, M. Puntoni, M. Colozza, U. Pfeffer, and P. Bruzzi
HER2 Status and Efficacy of Adjuvant Anthracyclines in Early Breast Cancer: A Pooled Analysis of Randomized Trials
J Natl Cancer Inst, January 2, 2008; 100(1): 14 - 20.
[Abstract] [Full Text] [PDF]

Home page
 Am Soc Clin Oncol Ed BookHome page
A. Di Leo, S. Licitra, W. Claudino, and L. Biganzoli
Molecular Predictors of Response to Anthracyclines
ASCO Educational Book, January 1, 2008; 2008(1): 3 - 7.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
L. Harris, H. Fritsche, R. Mennel, L. Norton, P. Ravdin, S. Taube, M. R. Somerfield, D. F. Hayes, and R. C. Bast Jr
American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer
J. Clin. Oncol., November 20, 2007; 25(33): 5287 - 5312.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
P. Lonning, S Knappskog, V Staalesen, R Chrisanthar, and J. Lillehaug
Breast cancer prognostication and prediction in the postgenomic era
Ann. Onc., August 1, 2007; 18(8): 1293 - 1306.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Z. Q. Yang, K. L. Streicher, M. E. Ray, J. Abrams, and S. P. Ethier
Multiple Interacting Oncogenes on the 8p11-p12 Amplicon in Human Breast Cancer
Cancer Res., December 15, 2006; 66(24): 11632 - 11643.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
M Tretiakova, M Turkyilmaz, T Grushko, M Kocherginsky, C Rubin, B Teh, and X J Yang
Topoisomerase II{alpha} in Wilms' tumour: gene alterations and immunoexpression
J. Clin. Pathol., December 1, 2006; 59(12): 1272 - 1277.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
M. Tanner, J. Isola, T. Wiklund, B. Erikstein, P. Kellokumpu-Lehtinen, P. Malmstrom, N. Wilking, J. Nilsson, and J. Bergh
Topoisomerase II{alpha} Gene Amplification Predicts Favorable Treatment Response to Tailored and Dose-Escalated Anthracycline-Based Adjuvant Chemotherapy in HER-2/neu-Amplified Breast Cancer: Scandinavian Breast Group Trial 9401
J. Clin. Oncol., June 1, 2006; 24(16): 2428 - 2436.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. U. Buzdar
Topoisomerase II{alpha} Gene Amplification and Response to Anthracycline-Containing Adjuvant Chemotherapy in Breast Cancer
J. Clin. Oncol., June 1, 2006; 24(16): 2409 - 2411.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. Tinari, R. Lattanzio, C. Natoli, E. Cianchetti, D. Angelucci, E. Ricevuto, C. Ficorella, P. Marchetti, S. Alberti, M. Piantelli, et al.
Changes of Topoisomerase II{alpha} Expression in Breast Tumors after Neoadjuvant Chemotherapy Predicts Relapse-Free Survival
Clin. Cancer Res., March 1, 2006; 12(5): 1501 - 1506.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
D. C. Marchion, E. Bicaku, J. G. Turner, A. I. Daud, D. M. Sullivan, and P. N. Munster
Synergistic Interaction between Histone Deacetylase and Topoisomerase II Inhibitors Is Mediated through Topoisomerase II{beta}
Clin. Cancer Res., December 1, 2005; 11(23): 8467 - 8475.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
J. A. Menendez, L. Vellon, R. Colomer, and R. Lupu
Effect of {gamma}-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene
J Natl Cancer Inst, November 2, 2005; 97(21): 1611 - 1615.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
M. Colozza, E. Azambuja, F. Cardoso, C. Sotiriou, D. Larsimont, and M. J. Piccart
Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now?
Ann. Onc., November 1, 2005; 16(11): 1723 - 1739.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. S. Knoop, H. Knudsen, E. Balslev, B. B. Rasmussen, J. Overgaard, K. V. Nielsen, A. Schonau, K. Gunnarsdottir, K. E. Olsen, H. Mouridsen, et al.
Retrospective Analysis of Topoisomerase IIa Amplifications and Deletions As Predictive Markers in Primary Breast Cancer Patients Randomly Assigned to Cyclophosphamide, Methotrexate, and Fluorouracil or Cyclophosphamide, Epirubicin, and Fluorouracil: Danish Breast Cancer Cooperative Group
J. Clin. Oncol., October 20, 2005; 23(30): 7483 - 7490.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
E. Bjorck, S. Ek, O. Landgren, M. Jerkeman, M. Ehinger, M. Bjorkholm, C. A. K. Borrebaeck, A. Porwit-MacDonald, and M. Nordenskjold
High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma
Blood, April 1, 2005; 105(7): 2908 - 2915.
[Abstract] [Full Text] [PDF]

Home page
 Jpn J Clin OncolHome page
J. M. Liu, L.-T. Chen, A. F. Y. Li, C. W. Wu, C. Lan, T. R. Chung, H.-S. Shiah, K. D. Lee, T. W. Liu, and J. W. Peng
Prognostic Implications of the Expression of erbB2, Topoisomerase II{alpha} and Thymidylate Synthase in Metastatic Gastric Cancer After Fluorouracil-based Therapy
Jpn. J. Clin. Oncol., December 1, 2004; 34(12): 727 - 732.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
V. Durbecq, M. Paesmans, F. Cardoso, C. Desmedt, A. Di Leo, S. Chan, K. Friedrichs, T. Pinter, S. Van Belle, E. Murray, et al.
Topoisomerase-II{alpha} expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel
Mol. Cancer Ther., October 1, 2004; 3(10): 1207 - 1214.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. A. Troester, K. A. Hoadley, T. Sorlie, B.-S. Herbert, A.-L. Borresen-Dale, P. E. Lonning, J. W. Shay, W. K. Kaufmann, and C. M. Perou
Cell-Type-Specific Responses to Chemotherapeutics in Breast Cancer
Cancer Res., June 15, 2004; 64(12): 4218 - 4226.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. ProteomicsHome page
J. S. Ross, J. A. Fletcher, K. J. Bloom, G. P. Linette, J. Stec, W. F. Symmans, L. Pusztai, and G. N. Hortobagyi
Targeted Therapy in Breast Cancer: The HER-2/neu Gene and Protein
Mol. Cell. Proteomics, April 1, 2004; 3(4): 379 - 398.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. P. Braybrooke, N. C. Levitt, S. Joel, T. Davis, S. Madhusudan, H. Turley, S. Wilner, A. L. Harris, and D. C. Talbot
Pharmacokinetic Study of Cisplatin and Infusional Etoposide Phosphate in Advanced Breast Cancer with Correlation of Response to Topoisomerase II{alpha} Expression
Clin. Cancer Res., October 15, 2003; 9(13): 4682 - 4688.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
J. S. Ross, J. A. Fletcher, G. P. Linette, J. Stec, E. Clark, M. Ayers, W. F. Symmans, L. Pusztai, and K. J. Bloom
The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy
Oncologist, August 1, 2003; 8(4): 307 - 325.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
A J Lodge, J J Anderson, W J Gullick, B Haugk, R C F Leonard, and B Angus
Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-erbB-4
J. Clin. Pathol., April 1, 2003; 56(4): 300 - 304.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Park and C. D. James
Lanthionine Synthetase Components C-like 2 Increases Cellular Sensitivity to Adriamycin by Decreasing the Expression of P-Glycoprotein through a Transcription-mediated Mechanism
Cancer Res., February 1, 2003; 63(3): 723 - 727.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. Climent, J. A. Martinez-Climent, D. Blesa, M. J. Garcia-Barchino, R. Saez, D. Sanchez-Izquierdo, P. Azagra, A. Lluch, and J. Garcia-Conde
Genomic Loss of 18p Predicts an Adverse Clinical Outcome in Patients with High-Risk Breast Cancer
Clin. Cancer Res., December 1, 2002; 8(12): 3863 - 3869.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Takahashi, X. J. Yang, T. T. Lavery, K. A. Furge, B. O. Williams, M. Tretiakova, A. Montag, N. J. Vogelzang, G. G. Re, A. J. Garvin, et al.
Gene Expression Profiling of Favorable Histology Wilms Tumors and Its Correlation with Clinical Features
Cancer Res., November 15, 2002; 62(22): 6598 - 6605.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
P. S. Bernard and C. T. Wittwer
Real-Time PCR Technology for Cancer Diagnostics
Clin. Chem., August 1, 2002; 48(8): 1178 - 1185.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. Di Leo, D. Gancberg, D. Larsimont, M. Tanner, T. Jarvinen, G. Rouas, S. Dolci, J.-Y. Leroy, M. Paesmans, J. Isola, et al.
HER-2 Amplification and Topoisomerase II{alpha} Gene Aberrations as Predictive Markers in Node-positive Breast Cancer Patients Randomly Treated Either with an Anthracycline-based Therapy or with Cyclophosphamide, Methotrexate, and 5-Fluorouracil
Clin. Cancer Res., May 1, 2002; 8(5): 1107 - 1116.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. S. Coon, E. Marcus, S. Gupta-Burt, S. Seelig, K. Jacobson, S. Chen, V. Renta, G. Fronda, and H. D. Preisler
Amplification and Overexpression of Topoisomerase II{alpha} Predict Response to Anthracycline-based Therapy in Locally Advanced Breast Cancer
Clin. Cancer Res., April 1, 2002; 8(4): 1061 - 1067.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
C. A. Iacobuzio-Donahue, A. Maitra, G. L. Shen-Ong, T. van Heek, R. Ashfaq, R. Meyer, K. Walter, K. Berg, M. A. Hollingsworth, J. L. Cameron, et al.
Discovery of Novel Tumor Markers of Pancreatic Cancer using Global Gene Expression Technology
Am. J. Pathol., April 1, 2002; 160(4): 1239 - 1249.
[Abstract] [Full Text] [PDF]

Home page
 J Natl Cancer Inst MonogrHome page
P. M. Ravdin
Is Her2 of Value in Identifying Patients Who Particularly Benefit From Anthracyclines During Adjuvant Therapy? A Qualified Yes.
J Natl Cancer Inst Monographs, December 1, 2001; 2001(30): 80 - 84.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Tanner, P. Jarvinen, and J. Isola
Amplification of HER-2/neu and Topoisomerase II{alpha} in Primary and Metastatic Breast Cancer
Cancer Res., July 1, 2001; 61(14): 5345 - 5348.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. N. Harris, L. Yang, V. Liotcheva, S. Pauli, J. D. Iglehart, O. M. Colvin, and T. S. Hsieh
Induction of Topoisomerase II Activity after ErbB2 Activation Is Associated with a Differential Response to Breast Cancer Chemotherapy
Clin. Cancer Res., June 1, 2001; 7(6): 1497 - 1504.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
K. J. Murphy, K. R. Nielson, and K. H. Albertine
Defining a Molecularly Normal Colon
J. Histochem. Cytochem., May 1, 2001; 49(5): 667 - 668.
[Abstract] [Full Text]

Home page
 JCOHome page
H. Yamauchi, V. Stearns, and D. F. Hayes
When Is a Tumor Marker Ready for Prime Time? A Case Study of c-erbB-2 as a Predictive Factor in Breast Cancer
J. Clin. Oncol., April 15, 2001; 19(8): 2334 - 2356.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2000 by the American Society for Investigative Pathology.