Mechanisms of Gefitinib-mediated reversal of tamoxifen resistance in MCF-7 breast cancer cells by inducing ERα re-expression

Estrogen receptor (ER)-positive breast cancer patients may turn ER-negative and develop acquired drug resistance, which compromises the efficacy of endocrine therapy. By investigating the phenomenon that gefitinib can re-sensitise tamoxifen (TAM)-resistant MCF-7 breast cancer cells (MCF-7/TAM) to TAM, the present study verified that gefitinib could reverse the acquired drug resistance in endocrine therapy and further explored the underlying mechanism. ER alpha-negative MCF-7/TAM cells were established. Upon treating the cells with gefitinib, the mRNA and protein levels of ER alpha and ER beta, as well as the expression of molecules involved in the MAPK pathway, were examined using the RT-PCR and immunocytochemistry. The RT-PCR results showed that the mRNA levels of ER alpha and ER beta in MCF-7/TAM cells were up-regulated following gefitinib treatment; specifically, ER alpha was re-expressed, and ER beta expression was up-regulated. The expression of molecules involved in the MAPK pathway, including RAS, MEK1/2, and p-ERK1/2, in MCF-7/TAM cells was significantly up-regulated, compared with MCF-7 cells. After the gefitinib treatment, the expression levels of MEK1/2 and p-ERK1/2 were significantly down-regulated. ER alpha loss is the primary cause for TAM resistance. Gefitinib reverses TAM resistance primarily by up-regulating the ER alpha mRNA level and inducing the re-expression of ER alpha. The MAPK pathway plays a key role in ER alpha re-expression.