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MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ER alpha Positive Breast Cancer
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SYSNO ASEP 0492940 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ER alpha Positive Breast Cancer Author(s) Lettlová, Sandra (BTO-N)
Brynychová, V. (CZ)
Blecha, Jan (BTO-N)
Vrána, D. (CZ)
Vondrusová, Magdaléna (BTO-N) RID
Souček, P. (CZ)
Truksa, Jaroslav (BTO-N) RID, ORCIDNumber of authors 7 Source Title Cellular Physiology and Biochemistry. - : Cellular Physiology and Biochemistry - ISSN 1015-8987
Roč. 46, č. 6 (2018), s. 2601-2615Number of pages 15 s. Language eng - English Country CH - Switzerland Keywords Breast cancer ; Estrogen dependence ; MiR-301a Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology R&D Projects GA13-28830S GA ČR - Czech Science Foundation (CSF) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support BTO-N - RVO:86652036 UT WOS 000433251900035 EID SCOPUS 85047163482 DOI 10.1159/000489687 Annotation Background/Aims: MiRNA-301a-3p is an oncogenic miRNA whose expression is associated with tumor development, metastases and overall poor prognosis. Estrogen receptor a (ERa) is one of the estrogen hormone-activated transcription factors, which regulates a large number of genes and is involved in the mammary gland development. Expression of ERa is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERa in breast cancer patients indicates invasiveness and poor prognosis. In this study, we focus on the regulation of ERa by miR-301a and its role in transition from estrogen-dependent to estrogen-independent breast cancer. Methods: Expression of miR-301a-3p was measured by qRT-PCR in tumor tissue samples from 111 patients with primary breast carcinoma and in mammospheres representing in vitro model of cancer stem-like cells. Dual reporter luciferase assay and complementary experiments were performed to validate ESR1 as a direct target of miR-301a-3p. The effect of miR-301a-3p on estrogen signaling was evaluated on the level of gene and protein expression and growth response to estrogens. Finally, the effect of mi R 301a-3p expression on tumor growth was studied in nude mice. Results: We identified ESR1 as a direct target of miR-301a-3p. Ectopic miR-301a-3p causes a decrease in ESR1 mRNA and protein level and modulates the expression of ERa target genes in ERa positive breast cancer cells. Consistently, miR-301a-3p causes a decrease in sensitivity of MCF7 cells to 17 beta-estradiol and inhibits the growth of estrogen dependent tumor in nude mice. Yet, the mice tumors have significantly increased expression of genes related to cancer stem-like cells and epithelial to mesenchymal transition suggesting enrichment of the population of cells with more invasive properties, in line with our observation that miR-301a-3p expression is highly increased in mammospheres which show a decrease in estrogenic signaling. Importantly, miR-301a-3P level is also increased in primary breast cancer samples exhibiting an ER/PR negative phenotype. Conclusion: Our results confirm ESR1 as a direct target of miR-301a-3p and suggest that mi R 301a3p likely contributes to development of estrogen independence, which leads to a more invasive phenotype of breast cancer. (C) 2018 The Author(s) Published by S. Karger AG, Basel Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2019
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