let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in breast cancer.

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.

• Authors: Yingchun Zhao, Caishu Deng, Weida Lu, Jing Xiao, Danjun Ma, Mingxi Guo, Robert R Recker, Zoran Gatalica, Zhaoyi Wang, Gary Guishan Xiao
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 17 Issue 11-12 Pg. 1233-41 ( 2011) ISSN: 1528-3658 [Electronic] England
• PMID: 21826373 (Publication Type: Journal Article)

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• MicroRNAs
• mirnlet7 microRNA, human
• Tamoxifen
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Base Sequence
• Breast Neoplasms (drug therapy, genetics)
• Cell Line, Tumor
• Down-Regulation (drug effects, genetics)
• Drug Screening Assays, Antitumor
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Genome, Human (genetics)
• Humans
• MicroRNAs (genetics, metabolism)
• Models, Biological
• Molecular Sequence Data
• Receptor, ErbB-2 (metabolism)
• Signal Transduction (drug effects, genetics)
• Tamoxifen (pharmacology, therapeutic use)
• Transfection