This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harris, L. N. Articles by Hsieh, T. S. Search for Related Content PubMed PubMed Citation Articles by Harris, L. N. Articles by Hsieh, T. S.

Induction of Topoisomerase II Activity after ErbB2 Activation Is Associated with a Differential Response to Breast Cancer Chemotherapy

Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [L. N. H.]; Department of Medicine [L. Y., V. L., S. P.], Comprehensive Cancer Center [O. M. C.], and Department of Biochemistry [T. S. H.], Duke University Medical Center, Durham, North Carolina 27710; and Department of Surgery, Brigham & Women’s Hospital, Boston, Massachusetts 02115 [J. D. I.]

ErbB2 (HER-2) gene amplification and overexpression have been shown to predict a better outcome with doxorubicin-based chemotherapy as opposed to alkylator-based chemotherapy in early stage breast cancer. To understand the mechanism of differential response to these two regimens, we have evaluated the effect of signaling through the ErbB2 receptor on downstream enzymes that may affect drug response, using two different models. The first system employs breast cancer cells that have high levels of endogenous ErbB2 by gene amplification (BT-474 and SKBR3 cells). The second system allows us to isolate the effect of ErbB2 receptor-mediated intracellular signaling using an epidermal growth factor receptor-ErbB2 chimeric receptor activated by epidermal growth factor. Our experiments show that the cytotoxicity of doxorubicin is inhibited in ErbB2+ breast cancer cells by the anti-ErbB2 antibody, Herceptin. This is accompanied by a decrease in topoisomerase (topo) II protein and activity, suggesting that this is the mechanism of change in doxorubicin response. In addition, a 10–100-fold (1–2 log) decrease in the LD₅₀ of doxorubicin is seen after ErbB2 activation using the chimeric receptor model. Furthermore, we see a 100-fold decrease in the LD₅₀ of etoposide, another topo II inhibitor. This increase in doxorubicin sensitivity is associated with a 4.5-fold increase in the amount of topo II protein and an increase in topo II activity as measured by DNA decatenating and unknotting activities, as well as cleavable complex formation. In contradistinction to doxorubicin, we have observed an increased resistance to cyclophosphamide chemotherapy after chimeric receptor activation. We propose that the differential benefit seen with doxorubicin- versus alkylator-based chemotherapy in ErbB2+ breast cancer is due, in some cases, to ErbB2-mediated topo II activation. These data also suggest hypotheses for the optimal sequencing of Herceptin and chemotherapy agents in ErbB2+ breast cancer.

This article has been cited by other articles:

				X. Zeng, D. Sachdev, H. Zhang, M. Gaillard-Kelly, and D. Yee Sequencing of Type I Insulin-Like Growth Factor Receptor Inhibition Affects Chemotherapy Response In vitro and In vivo Clin. Cancer Res., April 15, 2009; 15(8): 2840 - 2849. [Abstract] [Full Text] [PDF]

				J. S. Ross, E. A. Slodkowska, W. F. Symmans, L. Pusztai, P. M. Ravdin, and G. N. Hortobagyi The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti-HER-2 Therapy and Personalized Medicine Oncologist, April 1, 2009; 14(4): 320 - 368. [Abstract] [Full Text] [PDF]

				M. Dowsett and A. K. Dunbier Emerging Biomarkers and New Understanding of Traditional Markers in Personalized Therapy for Breast Cancer Clin. Cancer Res., December 15, 2008; 14(24): 8019 - 8026. [Abstract] [Full Text] [PDF]

				K. E. Coldwell, S. M. Cutts, T. J. Ognibene, P. T. Henderson, and D. R. Phillips Detection of Adriamycin-DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations Nucleic Acids Res., September 1, 2008; 36(16): e100 - e100. [Abstract] [Full Text] [PDF]

				M. P. DiGiovanna, D. F. Stern, S. Edgerton, G. Broadwater, L. G. Dressler, D. R. Budman, I. C. Henderson, L. Norton, E. T. Liu, H. B. Muss, et al. Influence of Activation State of ErbB-2 (HER-2) on Response to Adjuvant Cyclophosphamide, Doxorubicin, and Fluorouracil for Stage II, Node-Positive Breast Cancer: Study 8541 From the Cancer and Leukemia Group B J. Clin. Oncol., May 10, 2008; 26(14): 2364 - 2372. [Abstract] [Full Text] [PDF]

				J. M.S. Bartlett, I. O. Ellis, M. Dowsett, E. A. Mallon, D. A. Cameron, S. Johnston, E. Hall, R. A'Hern, C. Peckitt, J. M. Bliss, et al. Human Epidermal Growth Factor Receptor 2 Status Correlates With Lymph Node Involvement in Patients With Estrogen Receptor (ER) Negative, but With Grade in Those With ER-Positive Early-Stage Breast Cancer Suitable for Cytotoxic Chemotherapy J. Clin. Oncol., October 1, 2007; 25(28): 4423 - 4430. [Abstract] [Full Text] [PDF]

				N. Kopjar, I. Milas, V. Garaj-Vrhovac, and M. Gamulin Cytogenetic outcomes of adjuvant chemotherapy in non-target cells of breast cancer patients Human and Experimental Toxicology, May 1, 2007; 26(5): 391 - 399. [Abstract] [PDF]

				J. A. Menendez, I. Mehmi, and R. Lupu Trastuzumab in Combination With Heregulin-Activated Her-2 (erbB-2) Triggers a Receptor-Enhanced Chemosensitivity Effect in the Absence of Her-2 Overexpression J. Clin. Oncol., August 10, 2006; 24(23): 3735 - 3746. [Abstract] [Full Text] [PDF]

				N. Maqani, A. Belkhiri, C. Moskaluk, S. Knuutila, A. A. Dar, and W. El-Rifai Molecular Dissection of 17q12 Amplicon in Upper Gastrointestinal Adenocarcinomas Mol. Cancer Res., July 1, 2006; 4(7): 449 - 455. [Abstract] [Full Text] [PDF]

				P J Barrett-Lee Growth factor signalling in clinical breast cancer and its impact on response to conventional therapies: a review of chemotherapy Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S125 - S133. [Abstract] [Full Text] [PDF]

				A. U. Buzdar, N. K. Ibrahim, D. Francis, D. J. Booser, E. S. Thomas, R. L. Theriault, L. Pusztai, M. C. Green, B. K. Arun, S. H. Giordano, et al. Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer J. Clin. Oncol., June 1, 2005; 23(16): 3676 - 3685. [Abstract] [Full Text] [PDF]

				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]

				M. Masuda, M. Suzui, J. T. E. Lim, and I. B. Weinstein Epigallocatechin-3-gallate Inhibits Activation of HER-2/neu and Downstream Signaling Pathways in Human Head and Neck and Breast Carcinoma Cells Clin. Cancer Res., August 1, 2003; 9(9): 3486 - 3491. [Abstract] [Full Text] [PDF]

				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]

				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]

				A. Varis, M. Wolf, O. Monni, M.-L. Vakkari, A. Kokkola, C. Moskaluk, H. Frierson Jr., S. M. Powell, S. Knuutila, A. Kallioniemi, et al. Targets of Gene Amplification and Overexpression at 17q in Gastric Cancer Cancer Res., May 1, 2002; 62(9): 2625 - 2629. [Abstract] [Full Text] [PDF]

				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]