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

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

Research output: Contribution to journalArticle

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1233-1241
Number of pages9
JournalMolecular Medicine
Volume17
Issue number11
DOIs
StatePublished - Nov 2011

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Tamoxifen
MicroRNAs
Estrogen Receptors
Down-Regulation
Breast Neoplasms
MCF-7 Cells
Paraffin
Formaldehyde
Estrogens
Triple Negative Breast Neoplasms
Cell Line
Computational Biology
Luciferases
Reporter Genes
Transfection
Signal Transduction
Carcinogenesis
Breast
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in breast cancer. / Zhao, Yingchun; Deng, Caishu; Lu, Weida; Xiao, Jing; Ma, Danjun; Guo, Mingxi; Recker, Robert R.; Gatalica, Zoran; Wang, Zhaoyi; Xiao, Gary Guishan.

In: Molecular Medicine, Vol. 17, No. 11, 11.2011, p. 1233-1241.

Research output: Contribution to journalArticle

Zhao, Y, Deng, C, Lu, W, Xiao, J, Ma, D, Guo, M, Recker, RR, Gatalica, Z, Wang, Z & Xiao, GG 2011, 'Let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in breast cancer', Molecular Medicine, vol. 17, no. 11, pp. 1233-1241. https://doi.org/10.2119/molmed.2010.00225
Zhao, Yingchun ; Deng, Caishu ; Lu, Weida ; Xiao, Jing ; Ma, Danjun ; Guo, Mingxi ; Recker, Robert R. ; Gatalica, Zoran ; Wang, Zhaoyi ; Xiao, Gary Guishan. / Let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in breast cancer. In: Molecular Medicine. 2011 ; Vol. 17, No. 11. pp. 1233-1241.
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