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

Wang,Li-Juan; Han,Su-Xia; Bai,E; Zhou,Xia; Li,Meng; Jing,Gui-Hua; Zhao,Jing; Yang,An-Gang; Zhu,Qing

doi:10.3892/or.2013.2245

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

Authors:
- Li-Juan Wang
- Su-Xia Han
- E Bai
- Xia Zhou
- Meng Li
- Gui-Hua Jing
- Jing Zhao
- An-Gang Yang
- Qing Zhu
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Affiliations: Department of Oncology, The First Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China, Department of Immunology, the Fourth Military Medical University, Xi'an 710032, P.R. China
Published online on: January 21, 2013 https://doi.org/10.3892/or.2013.2245
Pages: 1563-1569

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Abstract

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 α subunit (Gαs) 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, Gαs 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.

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