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MiRNAs involved in LY6K and estrogen receptor ? contribute to tamoxifen-susceptibility in breast cancer.

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

SUBMITTER: Kim YS

PROVIDER: S-EPMC5173133 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Kim Ye Sol YS Park Sae Jeong SJ Lee Yeon Seon YS Kong Hyun Kyung HK Park Jong Hoon JH

Oncotarget 20160701 27

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), w ...[more]

PMID: 27304060

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Project description:Acquired tamoxifen (TAM) resistance limits the therapeutic benefit of TAM in patients with hormone-dependent breast cancer. The switch from estrogen-dependent to growth factor-dependent growth is a critical step in this process. However, the molecular mechanisms underlying this switch remain poorly understood. In this study, we established a TAM resistant cell sub line (MCF-7/TAM) from estrogen receptor-? (ER-?66) positive breast cancer MCF-7 cells by culturing ER-?66-positive MCF-7 cells in medium plus 1 ?M TAM over 6 months. MCF-7/TAM cells were then found to exhibit accelerated proliferation rate together with enhanced in vitro migratory and invasive ability. And the estrogen receptor-?36 (ER-?36), a novel 36-kDa variant of ER-?66, was dramatically overexpressed in this in vitro model, compared to the parental MCF-7 cells. Meanwhile, the expression of epidermal growth factor receptor (EGFR) in MCF-7/TAM cells was significantly up-regulated both in mRNA level and protein level, and the expression of ER-?66 was greatly down-regulated oppositely. In the subsequent studies, we overexpressed ER-?36 in MCF-7 cells by stable transfection and found that ER-?36 transfected MCF-7 cells (MCF-7/ER-?36) similarly exhibited decreased sensitivity to TAM, accelerated proliferative rate and enhanced in vitro migratory and invasive ability, compared to empty vector transfected MCF-7 cells (MCF-7/V). Real-time qPCR and Western blotting analysis revealed that MCF-7/ER-?36 cells possessed increased EGFR expression but decreased ER-?66 expression both in mRNA level and protein level, compared to MCF-7/V cells. This change in MCF-7/ER-?36 cells could be reversed by neutralizing anti-ER-?36 antibody treatment. Furthermore, knock-down of ER-?36 expression in MCF-7/TAM cells resulted in reduced proliferation rate together with decreased in vitro migratory and invasive ability. Decreased EGFR mRNA and protein expression as well as increased ER-?66 mRNA expression were also observed in MCF-7/TAM cells with down-regulated ER-?36 expression. In addition, blocking EGFR/ERK signaling in MCF-7/ER-?36 cells could restore the expression of ER-?66 partly, suggesting a regulatory function of EGFR/ERK signaling in down-regulation of ER-?66 expression. In conclusion, our results indicated for the first time a regulatory role of ER-?36 in up-regulation of EGFR expression and down-regulation of ER-?66 expression, which could be an underlying mechanism for the growth status switch in breast tumors that contribute to the generation of acquired TAM resistance. And ER-?36 could be considered a potential new therapeutic target in breast tumors which have acquired resistance to TAM.

Dataset Information

MiRNAs involved in LY6K and estrogen receptor ? contribute to tamoxifen-susceptibility in breast cancer.

Publications

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

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