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Let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor ? 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-?66, in the FFPE tissue set. Bioinformatic analysis suggested that ER-?36 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-?36 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-?36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Furthermore, ER-?36 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-?36 also exists in Tamoxifen (Tam)-resistant MCF7 cell line. Transfection of let-7 mimics to Tam-resistant MCF7 cells downregulated ER-?36 expression and enhanced the sensitivity of MCF7 cells to Tam in estrogen-free medium, which could be restored by overexpression of ER-?36 constructs without 3'UTR. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-?36 mediated nongenomic estrogen signal pathways and Tam resistance.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC3321804 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Zhao Yingchun Y Deng Caishu C Lu Weida W Xiao Jing J Ma Danjun D Guo Mingxi M Recker Robert R RR Gatalica Zoran Z Wang Zhaoyi Z Xiao Gary Guishan GG

Molecular medicine (Cambridge, Mass.) 20110727 11-12

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. ...[more]

PMID: 21826373

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Project description:IntroductionThe inhibition of estrogen receptor (ER) ? action with the ER antagonist tamoxifen is an established treatment in the majority of breast cancers. De novo or acquired resistance to this therapy is common. Expression of ER? in breast tumors has been implicated as an indicator of tamoxifen sensitivity. The mechanisms behind this observation remain largely uncharacterized. In the present study, we investigated whether ER? can modulate pathways implicated in endocrine resistance development.MethodsT47-D and MCF-7 ER?-expressing breast cancer cells with tetracycline-regulated expression of ER? were used as a model system. Expression levels and activity of known regulators of endocrine resistance were analyzed by performing quantitative polymerase chain reaction assays, Western blot analysis and immunostaining, and sensitivity to tamoxifen was investigated by using a cell proliferation kit.ResultsExpression of ER? in ER?-positive T47-D and MCF-7 human breast cancer cells resulted in a decrease in Akt signaling. The active form of an upstream regulator of Akt, proto-oncogene c-ErbB-2/receptor tyrosine kinase erbB-3 (HER2/HER3) receptor dimer, was also downregulated by ER?. Furthermore, ER? increased expression of the important inhibitor of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Importantly, ER? expression increased the sensitivity of these breast cancer cells to tamoxifen.ConclusionsOur results suggest a link between expression of ER? and endocrine sensitivity by increasing PTEN levels and decreasing HER2/HER3 signaling, thereby reducing Akt signaling with subsequent effects on proliferation, survival and tamoxifen sensitivity of breast cancer cells. This study supports initiatives to further investigate whether ER? presence in breast cancer samples is an indicator for endocrine response. Current therapies in ER?-positive breast cancers aim to impair ER? activity with antagonists or by removal of endogenous estrogens with aromatase inhibitors. Data from this study could be taken as indicative for also using ER? as a target in selected groups of breast cancer.

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

Publications

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

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