Abstract
The use of platinum complexes for the therapy of breast cancer is an emerging new treatment modality. To gain insight into the mechanisms underlying cisplatin resistance in breast cancer, we used estrogen receptor-positive MCF-7 cells as a model system. We generated cisplatin-resistant MCF-7 cells and determined the functional status of epidermal growth factor receptor (EGFR), MAPK, and AKT signaling pathways by phosphoreceptor tyrosine kinase and phospho-MAPK arrays. The cisplatin-resistant MCF-7 cells are characterized by increased EGFR phosphorylation, high levels of AKT1 kinase activity, and ERK1 phosphorylation. In contrast, the JNK and p38 MAPK modules of the MAPK signaling pathway were inactive. These conditions were associated with inactivation of the p53 pathway and increased BCL-2 expression. We investigated the expression of genes encoding the ligands for the ERBB signaling cascade and found a selective up-regulation of amphiregulin expression, which occurred at later stages of cisplatin resistance development. Amphiregulin is a specific ligand of the EGFR (ERBB1) and a potent mitogen for epithelial cells. After exposure to cisplatin, the resistant MCF-7 cells secreted amphiregulin protein over extended periods of time, and knockdown of amphiregulin expression by specific short interfering RNA resulted in a nearly complete reversion of the resistant phenotype. To demonstrate the generality and importance of our findings, we examined amphiregulin expression and cisplatin resistance in a variety of human breast cancer cell lines and found a highly significant correlation. In contrast, amphiregulin levels did not significantly correlate with cisplatin resistance in a panel of lung cancer cell lines. We have thus identified a novel function of amphiregulin for cisplatin resistance in human breast cancer cells.
Highlights
The use of platinum complexes for the therapy of breast carcinomas is an emerging new treatment modality that has recently been introduced into the clinical setting
We investigated the expression of genes encoding the ligands for the ERBB signaling cascade and found a selective up-regulation of amphiregulin expression, which occurred at later stages of cisplatin resistance development
For the therapy of HER2-overexpressing metastatic breast cancer, platinum complexes have been used in combination with paclitaxel and trastuzumab, a humanized monoclonal IgG1 that binds the extracellular domain of the ERBB2 (HER-2/neu) receptor [3]
Summary
EGFR (ERBB1), ERBB2 (HER-2), ERBB3, and ERBB4, and multiple ligands reviewed in Ref. 8. It is known that an extraordinary variety of different isoforms are produced from the NRG1 gene by alternative splicing. These isoforms include heregulins (HRGs), glial growth factors, and sensory motor neuron-derived factor. The development of cellular resistance to anticancer drugs is a dynamic biological process of high complexity. To better understand this clinically important issue, novel approaches like systems biology are needed. We systematically investigated the EGFR signaling system and related pathways, and we identified autocrine amphiregulin as a novel molecular mechanism that confers resistance to cisplatin. Examination of a panel of human breast cancer cells revealed that high levels of amphiregulin are associated with resistance to cisplatin demonstrating the generality of our findings
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