miRNAs involved in LY6K and estrogen receptor a contribute to tamoxifen-susceptibility in breast cancer

Estrogen receptor-alpha (ERa) is a clinically important therapeutic target for breast cancer. However, tumors that lose ERa are less responsive to anti-estrogens such as tamoxifen. MicroRNAs (miRNAs) are small RNAs that regulate expression of their target gene and dysregulations of miRNA has been identified in many diseases including human cancer. However, only a few miRNAs associated with tamoxifen resistance has been reported. In this study, we found that lymphocyte antigen 6 complex (LY6K), which is a member of the Ly-6/mu PAR superfamily and related to breast cancer progression and metastasis, is inversely correlated with ERa expression. We, for the first time, found miRNAs involved in the regulatory molecular mechanism between ERa and LY6K and related to tamoxifen susceptibility in breast cancer. miR-192-5p, induced by LY6K, downregulates ERa directly and induced tamoxifen resistance in ERa-positive breast cancer cells. In addition, re-expression of ERa in ERa-negative breast cancer cells increased miR-500a-3p expression and directly inhibits LY6K expression. Ectopic expression of miR-500a-3p sensitized ERa-negative cells to tamoxifen by increasing apoptosis. Finally, we observed an inverse correlation between LY6K and ERa in primary breast cancer samples. We found that patients with recurrence showed high expression of miR-192-5p after tamoxifen treatments. In addition, expression of miR-500a-3p was significantly correlated to survival outcome. As miRNAs involved in the regulatory mechanism between LY6K and ERa can affect tamoxifen resistance, downregulating miR-192-5p or re-expressing miR-500a-3p could be a potential therapeutic approach for treating tamoxifen resistant patients.