ABCG8-mediated sterol efflux increases cancer cell progression through LRP6/Wnt/beta-catenin signaling pathway in radiotherapy-resistant triple negative breast cancer cells (RT-R-TNBC), RT-R-MDA-MB-231
ATP-binding cassette (ABC) transporters are known to be increased in various tumor cells, including breast cancer. They are responsible for mediating drug resistance, leading to treatment failure. In the present study, gene expression array analysis revealed that among ABC transporter subtypes, ABCG8 was most increased in radiotherapy-resistant triple negative breast cancer (RT-R-TNBC) compared to TNBC. ABCG8 is known to be involved in sterol efflux, but its role in cancer is not well known. Therefore, we investigated the effect of ABCG8 on tumor progression in RT-R-TNBC. RT-R-MDA-MB-231 exhibited increased cholesterol levels in both cells and surrounding media by inducing SREBP1 and FASN. ABCG8 siRNA increased intracellular cholesterol but decreased media cholesterol, indicating an accumulation of cholesterol inside cells. Additionally, RT-R-MDA-MB-231 showed increased levels of ß-catenin, which was significantly reduced by ABCG8 knockdown. Moreover, ABCG8 knockdown led to cell cycle arrest in the G2/M phase by reducing PLK1 and Cyclin B1. RT-R-MDA-MB-231 also exhibited increased phosphor-LRP6 and LRP6 levels, which were decreased by ABCG8 siRNA. Interestingly, LRP6 siRNA decreased ß-catenin, PLK1, and Cyclin B1. In addition, feedback mechanisms such as LXR and IDOL were decreased in RT-R-MDA-MB-231 cells. This study suggests for the first time the role of ABCG8 and the cholesterol exported by ABCG8, not inside the cells, affects cancer progression through the LRP6/Wnt/beta-catenin signaling pathway in RT-R-TNBC. The regulation of this pathway may offer a potential therapeutic strategy for treating RT-R-TNBC. Overall design: RNA-seq profiling of MDA-MB-231 and radiotherapy resistant MDA-MB-231 (RT-R-MDA-MB-231)