[Involvement of epidermal growth factor receptor signaling pathway in tamoxifen resistance of MCF-7 cells]

Lin-Lin Zhen, Xun Zhu, Wei Zheng, Xuan-Yi Wang, Zheng-Yan Wu
Ai Zheng, Aizheng, Chinese Journal of Cancer 2006, 25 (7): 839-43

BACKGROUND & OBJECTIVE: Tamoxifen (TAM) is an important endocrine therapeutic drug used in combined treatment for breast cancer. However the drug resistant effect of TAM has become a major concern in clinical use. Epidermal growth factor receptor (EGFR) is expressed in many tumors and the expression of EGFR in breast cancer tissues is associated with poor prognosis. This study was to investigate EGFR signaling pathway in the drug resistant effect of TAM in breast cancer cells.

METHODS: An estrogen receptor (ER) positive breast cancer cell line, MCF-7 was incubated with TAM (10(-7) mol/L) for up to 6 months to produce drug resistant cells. mRNA and protein expression of EGFR signaling pathway related genes and ER gene was analyzed by fluorescent quantitation reverse transcription-polymerase chain reaction (fqRT-PCR) and Western blot. AG1478, an EGFR inhibitor, was also used to study the drug resistant effect of TAM.

RESULTS: The proliferation of MCF-7 cells was inhibited in the early stage after TAM treatment. However the inhibitory effect vanished after continuous 6-month treatment and the cell proliferation rate returned back to normal. The tolerance of MCF-7 cells to TAM was confirmed by cell growth inhibitory test. In TAM resistant MCF-7 cells, the expression of EGFR mRNA was increased by 4.5 times and the protein expression of EGFR, phosphorylation-extracellular signal-regulated kinase (p-ERK1/2) was also increased dramatically (P<0.05). While ER protein expression remained unchanged. Moreover the drug resistant cells were identified more sensitive to AG1478.

CONCLUSION: In endocrine therapy, TAM resistant breast cancer cells are likely to be generated by the activation of EGFR signaling pathway after long-term TAM treatment, and EGFR inhibitors might increase the therapeutic effects in breast cancer treatment.

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