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

The majority of breast cancers undergo progression from an initially endocrineresponsive phenotype to an endocrine therapy-resistant phenotype, and acquiredresistance to tamoxifen (Tam) is a major clinical problem. In the present study,we aimed to identify the function and mechanism of Tam at different concentrationsin cells with acquired Tam resistance. Estrogen-dependent MCF-7 cells were culturedwith Tam to generate Tam-resistant (TAM-R) breast cancer cells or in estrogen-freemedium to mimic the effects of clinical treatment. In addition, we analyzed theeffects of different concentrations of Tam on TAM-R cells by cell counting. Furthermore,the crosstalk between the stimulatory G protein α subunit (Gαs) and the activationof 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 agonistvia stimulation of the ERK1/2 signaling pathway, resulting in acquired resistanceto Tam, whereas high-dose Tam inhibited TAM-R cell growth by blocking the activationof ERK1/2 and AKT. Moreover, Gαs was involved in Tam resistance in breast cancercells. Taken together, our study demonstrated a dose-dependent growth responseto Tam in TAM-R cells, which will promote the understanding of the importanceof the appropriate use and dosage of Tam in the clinic.