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

Abstract

Estrogen receptor-alpha (ERα) is a clinically important therapeutic target for breast cancer. However, tumors that lose ERα 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/μPAR superfamily and related to breast cancer progression and metastasis, is inversely correlated with ERα expression. We, for the first time, found miRNAs involved in the regulatory molecular mechanism between ERα and LY6K and related to tamoxifen susceptibility in breast cancer. miR-192-5p, induced by LY6K, downregulates ERα directly and induced tamoxifen resistance in ERα-positive breast cancer cells. In addition, re-expression of ERα in ERα-negative breast cancer cells increased miR-500a-3p expression and directly inhibits LY6K expression. Ectopic expression of miR-500a-3p sensitized ERα-negative cells to tamoxifen by increasing apoptosis. Finally, we observed an inverse correlation between LY6K and ERα 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 ERα 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.

MiR-500a-3p inhibits cell proliferation and invasion by targeting lymphocyte antigen 6 complex locus K (LY6K) in human non-small cell lung cancer

“…There is evidence that miR-500a-3p correlates with poor response to therapy in patients with breast cancer [15]. Meanwhile, miR-500a-3p in ERα-negative breast cancer cells can be increased by ERα, and re-expressing miR-500a-3p could be a potential therapeutic approach for treating tamoxifen resistant patients [16]. Although some studies have reported that miR-500a was up-regulated in human cancers such as hepatocellular carcinoma and chronic lymphocytic cancer [21], little is known about miR-500a-3p's precise activity and the only existing studies suggest that miR-500a-3p can be increased or decreased in the progression of different tumors and promote or suppress tumor growth.…”

“…Examples include promoter miR-1271 by down-regulation of HOXA5 [13] and inhibitor miR-342-3p through repression of RAP2B [14]. Although MiR-500a-3p, combined with SNPs rs3732360, rs1054190 and rs1054191, correlates with poor response to therapy in patients with breast cancer and is down-regulated in doxorubicin treated cells [15], in ERα-negative breast cancer cells it can be increased by ERα re-expression, directly leading to inhibition of LY6K expression; and LY6K mRNA and protein expression is significantly reduced by ectopic miR-500a-3p [16]. Therefore, we hypothesize that miR-500a-3p can target LY6K and thus participate in the development of NSCLC.…”

miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma

“…A number of studies reported that dysregulation of miRNAs contributed to the tumorigenesis and progression of various kinds of cancers by regulating CSCs, including hepatocellular carcinoma [ 19 – 22 ]. miR-500a-3p, as one of the original miRNAs discovered, has been reported to be implicated in the chemotherapeutic resistance, invasion and migration via SFRP2, GSK-3β and LY6K in different types of cancers [ 23 , 24 ]. However, the biological roles of miR-500a-3p and the underlying molecular mechanisms responsible for HCC initiation and progression have not been reported.…”

hsa‐miR‐500a‐3P alleviates kidney injury by targeting MLKL‐mediated necroptosis in renal epithelial cells

“…Of these miRNAs, only miR-500a-3P was significantly reduced after toxic and hypoxic insults. miR-500a-3p appears to play roles in breast cancer, hepatocellular carcinoma, and endometriosis (23)(24)(25). A previous study also showed that miR-500 induces gastric cancer cell proliferation while preventing apoptosis, indicating that it is involved in the regulation of cell death (26).…”