Induction of topoisomerase II activity after ErbB2 activation is associated with a differential response to breast cancer chemotherapy.
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) IIalpha 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 LD(50) of doxorubicin is seen after ErbB2 activation using the chimeric receptor model. Furthermore, we see a 100-fold decrease in the LD(50) of etoposide, another topo II inhibitor. This increase in doxorubicin sensitivity is associated with a 4.5-fold increase in the amount of topo IIalpha 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 IIalpha activation. These data also suggest hypotheses for the optimal sequencing of Herceptin and chemotherapy agents in ErbB2+ breast cancer.
Harris
L N
LN
Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Yang
L
L
Liotcheva
V
V
Pauli
S
S
Iglehart
J D
JD
Colvin
O M
OM
Hsieh
T S
TS
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D003520:Cyclophosphamide / Q000494:pharmacology; D004247:DNA / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D004247:DNA; D004250:DNA Topoisomerases, Type II; D004317:Doxorubicin; D004815:Epidermal Growth Factor; D005047:Etoposide; D019384:Nucleic Acid Synthesis Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases