Dose-dependent effect of tamoxifen in tamoxifen-resistant breast cancer cells via stimulation by the ERK1/2 and AKT signaling pathways

摘要

The majority of breast cancers undergo progression from an initially endocrine responsive phenotype to an endocrine therapy-resistant phenotype, and acquired resistance to tamoxifen (Tam) is a major clinical problem. In the present study, we aimed to identify the function and mechanism of Tam at different concentrations in cells with acquired Tam resistance. Estrogen-dependent MCF-7 cells were cultured with Tam to generate Tam-resistant (TAM-R) breast cancer cells or in estrogen-free medium to mimic the effects of clinical treatment. In addition, we analyzed the effects of different concentrations of Tam on TAM-R cells by cell counting. Furthermore, the crosstalk between the stimulatory G protein a subunit (Gas) and the activation of ERK1/2 and AKT in TAM-R cells was examined by small interfering RNA (siRNA) and immunoblotting methods. Low-dose Tam was found to act as an estrogen agonist via stimulation of the ERK1/2 signaling pathway, resulting in acquired resistance to Tam, whereas high-dose Tam inhibited TAM-R cell growth by blocking the activation of ERK1/2 and AKT. Moreover, Gas was involved in Tam resistance in breast cancer cells. Taken together, our study demonstrated a dose-dependent growth response to Tam in TAM-R cells, which will promote the understanding of the importance of the appropriate use and dosage of Tam in the clinic.