Abstract
Innate and acquired tamoxifen (TAM) resistance in estrogen receptor positive (ER+) breast cancer is an important problem in adjuvant endocrine therapy. The underlying mechanisms of TAM resistance is yet unknown. In the present study, we evaluated the role of renin–angiotensin system (RAS) in the acquisition of TAM resistance in human breast cancer cell line MCF-7, and the potential role of captopril and captopril+losartan combination in the prevention and reversion of the TAM resistant phenotype. MCF-7 cells were continuously exposed to 1μmol/L TAM to develop TAM resistant cells (TAM-R). MTT cell viability assay was used to determine the growth response of MCF-7 and TAM-R cells, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess angiotensin I converting enzyme (ACE), angiotensin II receptor type-1 and type-2 (AGTR1 and AGTR2) mRNA expressions. Preventive and therapeutic effects of RAS blockers – captopril and losartan – were examined on MCF-7 and TAM-R cells. Based on qRT-PCR, TAM-R cells compared to MCF-7 cells, had a mean±SD fold increase of 319.1±204.1 (P=0.002) in production of ACE mRNA level, 2211.8±777.9 (P=0.002) in AGTR1 mRNA level, and 265.9±143.9 (P=0.037) in production of AGTR2 mRNA level. The combination of either captopril or captopril+losartan with TAM led to the prevention and even reversion of TAM resistant phenotype.
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