Effect of angiotensin receptor blockade on prevention and reversion of tamoxifen-resistant phenotype in MCF-7 cells
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Tamoxifen (TAM) is a standard adjuvant endocrine therapy in postmenopausal breast cancer patients, but innate or acquired TAM resistance has remained to be a therapeutic challenge for clinicians. The aim of this study was to explore the possible participation of renin-angiotensin system (RAS) in the acquisition of TAM resistance and try to prevent and regress the resistance using an angiotensin II receptor type-1 (AGTR1) blocker, losartan. Establishment of TAM-resistant (TAM-R) cells was accomplished by continuous exposure of MCF-7 cells to 1 μmol/L TAM. MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to determine cell growth. Moreover, messenger RNA (mRNA) expression levels of AGTR1 and angiotensin II receptor type-2 (AGTR2) were measured by quantitative real-time polymerase chain reaction. A significant increase of AGTR1 and AGTR2 transcripts was observed in TAM-R cells compared to MCF-7 cells. Interestingly, losartan-TAM combination effectively resensitized TAM-R cells to tamoxifen treatment by inducing cell death. Therefore, our findings suggest an important role of RAS in acquired TAM resistance and targeting of RAS by losartan may overcome TAM resistance phenomenon and provide a novel avenue for treatment of resistant breast cancers.
KeywordsBreast cancer Tamoxifen resistance Renin-angiotensin system Losartan MCF-7
This study was financially supported by grants from Shiraz University of Medical Sciences (no. 91-01-36-4902), Iran National Science Foundation (no. 90003070), and Institute for Cancer Research (ICR). The funding sources only financially supported this study and were not involved in the study design, data analysis, interpretation of data, writing, editing, and submission of the manuscript. This work contains parts of the doctoral thesis of Ebrahim Sahebi. The authors would like to thank Dr. Shirin Ardeshir-Rouhani-Fard for proof reading the manuscript.
Conflicts of interest
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