miRNAs involved in LY6K and estrogen receptor α contribute to tamoxifen-susceptibility in breast cancer.
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.
Department of Biological Science, Sookmyung Women's University, Seoul, Korea.
Ye Sol
YS
Kim
Department of Biological Science, Sookmyung Women's University, Seoul, Korea.
Sae Jeong
SJ
Park
Department of Biological Science, Sookmyung Women's University, Seoul, Korea.
Yeon Seon
YS
Lee
Department of Biological Science, Sookmyung Women's University, Seoul, Korea.
Hyun Kyung
HK
Kong
Department of Biological Science, Sookmyung Women's University, Seoul, Korea.
Jong Hoon
JH
Park
D020413:3' Untranslated Regions; D000950:Antigens, Ly / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
D020413:3' Untranslated Regions; D000950:Antigens, Ly; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D058851:GPI-Linked Proteins; C525725:LY6K protein, human; C546783:MIRN192 microRNA, human; C547054:MIRN500 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D013629:Tamoxifen
ERα; LY6K; breast cancer; miRNA; tamoxifen susceptibility