let-7 MicroRNAs Induce Tamoxifen Sensitivity by Downregulation of Estrogen Receptor α Signaling in Breast Cancer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-07-27

AUTHORS

Yingchun Zhao, Caishu Deng, Weida Lu, Jing Xiao, Danjun Ma, Mingxi Guo, Robert R. Recker, Zoran Gatalica, Zhaoyi Wang, Gary Guishan Xiao

ABSTRACT

MicroRNAs (miRNAs) play an important regulatory role in breast tumorigenesis. Previously, we found that let-7 miRNAs were downregulated significantly in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. In this study, we further found that endogenous levels of let-7b and let-7i miRNAs are inversely correlated with levels of estrogen receptor (ER)-a36, a new variant of ER-α66, in the FFPE tissue set. Bioinformatic analysis suggested that ER-α36 may be another target of let-7 miRNAs. To test this hypothesis, cotransfection of let-7 mimics or inhibitors together with full-length or a fragment of ER-α36 3′UTR luciferase construct was performed, and we found that let-7b and let-7i mimics suppressed the activity of reporter gene significantly, which was enhanced remarkably by let-7b and let-7i inhibitors. Both mRNA and protein expression of ER-α36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Furthermore, ER-α36 mediated nongenomic MAPK and Akt pathways were weakened by let-7b and let-7i mimics in triple negative breast cancer cell line MDA-MB-231. The reverse correlation between let-7 miRNAs and ER-α36 also exists in Tamoxifen (Tam)-resistant MCF7 cell line. Transfection of let-7 mimics to Tam-resistant MCF7 cells downregulated ER-α36 expression and enhanced the sensitivity of MCF7 cells to Tam in estrogen-free medium, which could be restored by overexpression of ER-α36 constructs without 3′UTR. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-α36 mediated nongenomic estrogen signal pathways and Tam resistance. More... »

PAGES

1233-1241

Identifiers

URI

http://scigraph.springernature.com/pub.10.2119/molmed.2010.00225

DOI

http://dx.doi.org/10.2119/molmed.2010.00225

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21826373


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77 let-7 miRNAs
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79 levels
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81 luciferase construct
82 mRNA
83 mechanism
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85 miRNA
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87 microRNAs
88 mimics
89 new variant
90 novel regulatory mechanism
91 overexpression
92 paraffin-embedded breast cancer tissues
93 pathway
94 protein expression
95 receptor α
96 receptors
97 regulatory mechanisms
98 regulatory role
99 reporter gene
100 resistance
101 results
102 reverse correlation
103 role
104 sensitivity
105 signal pathway
106 study
107 tamoxifen
108 tamoxifen sensitivity
109 target
110 tissue
111 transfection
112 triple-negative breast cancer cell line MDA-MB-231
113 tumorigenesis
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