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MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ER alpha Positive Breast Cancer

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F18%3A00492940" target="_blank" >RIV/86652036:_____/18:00492940 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/61989592:15110/18:73590326 RIV/75010330:_____/18:00012161

  • Výsledek na webu

    <a href="http://dx.doi.org/10.1159/000489687" target="_blank" >http://dx.doi.org/10.1159/000489687</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1159/000489687" target="_blank" >10.1159/000489687</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ER alpha Positive Breast Cancer

  • Popis výsledku v původním jazyce

    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

  • Název v anglickém jazyce

    MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ER alpha Positive Breast Cancer

  • Popis výsledku anglicky

    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

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10601 - Cell biology

Návaznosti výsledku

  • Projekt

    Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

  • Návaznosti

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Ostatní

  • Rok uplatnění

    2018

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Cellular Physiology and Biochemistry

  • ISSN

    1015-8987

  • e-ISSN

  • Svazek periodika

    46

  • Číslo periodika v rámci svazku

    6

  • Stát vydavatele periodika

    CH - Švýcarská konfederace

  • Počet stran výsledku

    15

  • Strana od-do

    2601-2615

  • Kód UT WoS článku

    000433251900035

  • EID výsledku v databázi Scopus

    2-s2.0-85047163482