Abstract
Although extensively studied, the mechanisms by which estrogen promotes breast cancer growth remain to be fully elucidated. Tamoxifen, an antiestrogen to treat ERα+ breast cancer, is also a high-affinity blocker of the chloride channels. In this study, we explored the involvement of the chloride channels in the action of estrogen in breast cancer. We found that 17β-estradiol (17β-E2) concentration-dependently activated the chloride currents in ERα+ breast cancer MCF-7 cells. Extracellular hypertonic challenge and chloride channel blockers, NPPB and DIDS inhibited the 17β-E2-activated chloride currents. Decreased the ClC-3 protein expression caused the depletion of the 17β-E2-activated chloride currents. 17β-E2-activated chloride currents which relied on the ERα expression were demonstrated by the following evidences. Firstly, 17β-E2-activated chloride currents could not be observed in ERα- breast cancer MDA-MB-231 cells. Secondly, ER antagonists, tamoxifen and ICI 182,780, and downregulation of ERα expression inhibited or abolished the 17β-E2-activated chloride currents. Thirdly, ERα expression was induced in MDA-MB-231 cells by ESR1 gene transfection, and then 17β-E2-activated chloride currents could be observed. In MCF-7 cells, ERα and ClC-3 mainly located in nucleus and translocated to cell plasma and membrane with respect to co-localization following treatment of 17β-E2. Downregulation of ERα expression could decrease the expression of ClC-3 protein. Conversely, downregulation of ClC-3 expression did not influence the ERα expression. Taken together, our findings demonstrated that ClC-3 is a potential target of 17β-E2 and modulates by the ERα in breast cancer cell. Pharmacological modulation of ClC-3 may provide a deep understanding in antiestrogen treatment of breast cancer patients. This article is protected by copyright. All rights reserved
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