Inhibition of EGFR and HER2 in Tamoxifen-resistant T47D:A18/4-OHT Breast Cancer Cells

ABSTRACT

PURPOSE: Tamoxifen has been prescribed as a very effective hormonal agent not only for the treatment of breast cancer, but also for the prevention of the disease. The development of resistance to tamoxifen is one of the most important obstacles to hormonal therapy of breast cancer. HER2 or EGFR expression has been reported to be associated with the development of tamoxifen resistance. This study was performed to evaluate the effect of HER2 and EGFR inhibition on tamoxifen resistance using tamoxifen-resistant breast cancer cells (T47DA18/4-OHT cells). METHODS: Tamoxifen-resistant T47DA18/4-OHT cells were established by long-term treatment of 1micrometer 4-hydroxytamoxifen on T47DA18 human breast cancer cells. The effect of HER2 and EGFR inhibition was investigated by the use of a cell proliferation assay with treatment of trastuzumab, a monoclonal antibody to the extracellular domain of the human HER2 receptor, and ZD1839, an ERFR tyrosine kinase inhibitor. RESULTS: In contrast to T47DA18 cells, T47DA18/4-OHT cells showed estrogen-independent proliferation and partial regulation by treatment with tamoxifen. With a single treatment of trastuzumab or ZD1839, T47DA18/4-OHT cell growth was reduced to 77.8% (P=0.15) or 74.4% (P=0.034) respectively, as compared to untreated cells. Combinational treatment with 1 nM estradiol resulted in a further reduction of T47DA17 cell proliferation by 83.6% (P=0.002) for trastuzumab and 77.7% (P=0.047) for ZD1839, as compared to the single treatments. CONCLUSION: Tamoxifen resistance could be partially regulated by inhibition of HER2 or EGFR in T47DA18/4-OHT cells, especially in combination with a low dose of estradiol. This effect may provide an important clue to overcome tamoxifen resistance in the treatment of breast cancer.