Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.

Cheng-Fei Jiang,Min-Min Liu,Zhu-Mei Shi,Bing-Hua Jiang,Ying-Chen Qian,Lin-Lin Zhen,Dong-Mei Li,Ling-Zhi Liu,Yi-Yang Wen,Jie Lin,Xue Liu,Xin Ge,Lin Wang

doi:10.18632/oncotarget.9230

Abstract

It is currently known that estrogen plays an important role in breast cancer (BC) development, but the underlying molecular mechanism remains to be elucidated. Accumulating evidence has revealed important roles of microRNAs in various kinds of human cancers, including BC. In this study, we found that among the microRNAs regulated by estrogen, miR-124 was the most prominent downregulated miRNA. miR-124 was downregulated by estradiol (E2) treatment in estrogen receptor (ER) positive BC cells, miR-124 overexpression suppressed cell proliferation, migration and invasion in BC cells; while the suppression of miR-124 using Anti-miR-124 inhibitor had opposite cellular functions. Under the E2 treatment, miR-124 had stronger effect to inhibit cellular functions in MCF7 cells than that in MDA-MB-231 cells. In addition, we identified that ERα, but not ERβ, was required for E2-induced miR-124 downregulation. Furthermore, AKT2, a known oncogene, was a novel direct target of miR-124. AKT2 expression levels were inversely correlated with miR-124 expression levels in human breast cancer specimens. AKT2 was overexpressed in BC specimens, and its expression levels were much higher in ERα positive cancer tissues than those ERα negative cancer tissues. Consistent with miR-124 suppression, E2 treatment increased AKT2 expression levels in MCF7 cells via ERα. Finally, overexpression of miR-124 in MCF7 cells significantly suppressed tumor growth and angiogenesis by targeting AKT2. Our results provide a mechanistic insight into a functional role of new ERα/miR-124/AKT2 signaling pathway in BC development. miR-124 and AKT2 may be used as biomarkers for ERα positive BC and therapeutic effect in the future.

Highlights

Breast cancer (BC) is one of the most common gynecological malignancies and estrogen receptor α (ERα) is expressed in about 75% of diagnosed breast tumors (ERα positive) [1, 2]
To explore whether estrogen regulates the expression of certain miRNAs in BC, the estrogen receptor positive breast cancer cells MCF7 were treated with 10nM E2 or isopyknic solvent ethyl alcohol (Eth) as control for 24h, the expression levels of miRNAs were detected by Quantitative reverse transcriptase (qRT)-PCR
To test whether E2 inhibits miR-124 expression through the function of ER, the ER-positive and ER-negative BC cells MCF7 and MDA-MB-231 were treated with E2 or Eth at different time points and the results showed that miR-124 expression was downregulated at 6, 12 and 24 h post E2 treatment in MCF7 cells (Figure 1B), but not in MDA-MB-231 cells (Figure 1C), suggesting that ER is necessary for E2 to inhibit miR-124 expression

Summary

Introduction

Breast cancer (BC) is one of the most common gynecological malignancies and estrogen receptor α (ERα) is expressed in about 75% of diagnosed breast tumors (ERα positive) [1, 2]. Growing evidence manifests that exposure to estrogens (estrone and estradiol) is an important determinant of BC risk, and ERα blockers have been widely used in clinic to treat BC [3, 4]. The expression of estrogen receptor β (ERβ), the other subunit of estrogen receptor, is reduced during tumorigenesis and is important in terminal differentiation of breast epithelial cells [5, 6]. Estrogen influences numerous cell signal pathways by activing ERα which is essential for the proliferation of a large subset of breast tumors [7,8,9].

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