Long non-coding RNA UCA1 enhances tamoxifen resistance in breast cancer cells through a miR-18a-HIF1α feedback regulatory loop

Recent studies reported that long non-coding RNAs (lncRNAs) might play critical roles in regulating endocrine resistance of breast cancer. Urothelial carcinoma-associated 1 (UCA1) is an lncRNA with an oncogenic role in breast cancer. This study aimed to investigate whether UCA1 is involved in acquired tamoxifen resistance in estrogen receptor (ER)-positive cancer cells. Our findings reveal that tamoxifen induces UCA1 upregulation in ER-positive breast cancer cells in a HIF1 alpha-dependent manner. UCA1 upregulation results in significantly enhanced tamoxifen resistance. The upregulated UCA1 sponges miR-18a, which is a negative regulator of HIF1 alpha. Therefore, UCA1 upregulation is further enhanced through a miR-18a-HIF1 alpha feedback loop. In addition, our data also showed that miR-18a is a modulator of tamoxifen sensitivity due to its regulative effect on cell cycle proteins. miR-18a inhibitor reduced the sensitivity of MCF-7 cells to tamoxifen, while miR-18a mimics sensitized BT474 cells to tamoxifen. Therefore, miR-18a downregulation also partly contributes to acquired tamoxifen resistance in the cancer cells. These findings provide some useful information for future clinical treatment of tamoxifen resistance.