Expression and function of miR-155 in breast cancer

Abstract

A major problem in the treatment of breast cancer at present is the lack of more sensitive and specific tumour biomarkers. MicroRNAs (miRNAs) were first discovered as important regulators of development in Caenorhabditis elegans, and their functions have been widely investigated. miR-155 is an oncogenic miRNA which has been explored mainly in leukaemia but is also known to play an important role in the progression of breast cancer. There is an accumulating body of evidence about additional roles of miR-155 in the development of breast cancer. In this mini-review, we provide an overview and update of miR-155 expression and its roles in breast cancer. We also attempt to summarize the current understanding of miR-155 regulation networks and speculate on the potential of miR-155 as a putative accessory parameter for diagnosis of breast cancer.

Keywords:

• miR-155
• breast cancer
• oncogenic miRNA
• target genes

Introduction

MicroRNAs (miRNAs) are small (22–25 nt) non-coding single-stranded RNAs that control the expression of target genes by suppressing translation or inducing the cleavage of target mRNAs.[1,2] miRNAs have been reported to be involved in the control of gene expression and to provide a broad regulatory role in various biological processes, including cancer development, cellular differentiation, proliferation, apoptosis and metabolism.[3–5]. Breast cancer is the most frequently diagnosed cancer with high mortality in females.[6] The incidence of mortality from breast cancer is associated with differences in reproductive and hormonal factors.[7] A major problem in the treatment of breast cancer at present is the lack of more sensitive and specific tumour biomarkers. In the clinic, there are only two markers that are well established and used in breast cancer diagnostics. One is estrogen receptor, the indication of endocrine therapy, and the other is epidermal growth factor receptor-2 (HER-2), which predicts the response to trastuzumab.[8] New biomarkers that can complement and improve the current methods for breast cancer diagnostics are urgently needed. MiRNAs were first discovered as important regulators of development in Caenorhabditis elegans and their functions have been widely investigated. miRNAs, such as miR-155,[9] may be suggested as novel potential diagnostic targets in cancer diagnostics. miR-155, which was first described by Clurman and Hayward in 1989 and reported to be involved in the progression of lymphoma [10], now has more than 400 predicted gene targets,[11] including over 100 confirmed ones. In the light of the sustained upregulation of miR-155 in breast cancer patients, we may hypothesize that miR-155 could be a diagnostic biomarker for breast cancer.

MiRNA and breast cancer

Recent advances in phenotyping and molecular profiling of human cancer have greatly enhanced the molecular mechanisms and diagnosis of breast cancer.[12] However, several problems, including unpredictable risk and resistance to drug treatment, still prevail in the management of breast cancer patients. In the process of carcinogenesis and cancer development, a multitude of transcription factors regulate the expression of miRNAs. At the same time, miRNAs function as regulators of target-gene expression involved in the cancer processes, which suggests that miRNAs could be considered potential biomarkers and therapeutic targets. As miRNAs were first identified as tumour suppressors, several miRNAs, such as miR-21 and miR-155, were revealed to exhibit oncogenic activity in the following years.[13,14] For review, see [15]. Half of the mature human miRNAs have been shown to be associated with cancer genes (reviewed in [16]). For example, miR-196 and miR-10a are located in homeobox clusters which are involved in the development of breast cancer.[17] These studies underline the importance and potential use of miRNAs as breast cancer classifiers and therapeutic targets.

Biosynthesis of miR-155

In humans, miR-155 is encoded by gene MIR155HG (also termed the B cell integration cluster, or BIC locus), which is located on chromosome 21. The primary miRNA molecule (pri-miR-155) is processed from the BIC gene RNA transcript. The pri-miR-155 molecule is first cleaved to be a precursor (pre-miR-155) by the Drosha and Pasha miRNA microprocessor in the nucleus. Then, pre-miR-155 is exported to the cytoplasm and transformed to mature miR-155 by the RNase III Dice (reviewed in [18]). Finally, mature miR-155 is incorporated into a miRNA-induced silencing complex, which binds to the sequences in the 3′-untranslated regions (3′-UTRs) of target mRNAs, including those for some key regulatory proteins such as Ras homolog family member A (RhoA), forkhead box O3A (FOXO3a) and suppressor of cytokine signalling 1 (SOCS1).[19,20] These genes in breast cancer can induce an increase in epithelial to mesenchymal cell transition, cell plasticity, cell survival, growth, chemo-resistance and radio-resistance.[19,20]

Expression of miR-155 in breast cancer

Several studies suggest that the expression of miR-155 is upregulated in breast cancer (Table 1). The high level of miR-155 is associated with tumour subtype and high mortality.[34] For example, a study on 29 miRNAs that are deregulated in breast cancer showed that only miR-155 is significantly upregulated,[7] suggesting that miR-155 plays an important role in breast cancer. In another larger study, serum miR-155 was also significantly increased in breast cancer patients compared with healthy ones.[30] A further study also indicated that the level of miR-155 is increased in breast cancer and suggested its potential clinical prognostic value. Higher miR-155 expression in breast cancer has been shown to be significantly associated with higher tumour grade, advanced tumour stage and lymph node metastasis, suggesting its potential as a clinical prognostic value.[35] For a review on circulating miRNAs as biomarkers in breast cancer, see [35].

Table 1. Studies identifying consistently upregulated miR-155 expression in breast cancer.

Country	Ethnicity	Samples	Source of controls	Genotyping method	Cases/control	Expression	Year	Reference
Canada	Caucasian	Tissues	Healthy people	TaqMan® density arrays	34/6	Up	2009	Hui et al. [21]
Germany	Caucasian	Serum	Healthy people	Real-time PCR	59/29	Up	2010	Roth et al. [22]
China	Asian	Tissues	Pericancerous tissues	MicroRNA microarray	8/8	Up	2008	Yan et al. [23]
China	Asian	Tissues	Healthy people	Real-time PCR	68/40	Up	2010	Wang et al. [24]
China	Asian	Tissues	Pericancerous tissues	Real-time PCR	45/45	Up	2010	Zhu et al. [25]
China	Asian	Tissues	Pericancerous tissues	Real-time PCR	45/45	Up	2011	Zheng et al. [26]
China	Asian	Serum	Healthy people	Real-time PCR	20/10	Up	2012	Liu et al. [27]
China	Asian	Tissues	Pericancerous tissues	Real-time PCR	92/92	Up	2012	Chen et al. [28]
China	Asian	Tissues/serum	Pericancerous tissues Healthy people	Real-time PCR	67/6767/70	Up	2012	Lu et al. [29]
China	Asian	Serum	Healthy people	Real-time PCR	103/55	Up	2012	Sun et al. [30]
Egypt	Egyptian	Tissues	Pericancerous tissues	Real-time PCR	40/40	Up	2012	Hafez et al. [31]
Italy	Caucasian	Tissues	Healthy people	MicroRNA microarray	76/34	Up	2005	Iorio et al. [7]
Italy	Caucasian	Tissues	Healthy people	MicroRNA microarray	363/177	Up	2006	Volinia et al. [32]
UK	Caucasian	Tissues	Healthy people	MicroRNA microarray	93/5	Up	2007	Blenkiron et al. [33]

Note: PCR: Polymerase chain reaction.

Regulation of miR-155 expression in breast cancer

Breast cancer 1 (BRCA1) is the most remarkable finding related to the role of miR-155 in breast cancer. BRCA1 is encoded by the human breast cancer susceptibility gene BRCA1 and is involved in DNA repair and cell cycle progression.[36] Mutations of BRCA1 are related to increased risk of breast cancer.[37] In a recent study, overexpression of miR-155 in BRCA1 wild-type cells showed a similar phenotype to the mutant, indicating that BRCA1 functions in the control of miR-155.[38] In addition, BRCA1 controls miR-155 expression by regulating the transcription of pri-miR-155.[38] A clinical study demonstrated that miR-155 levels are upregulated in human breast tumours with BRCA1 mutation.[38] This suggests that miR-155 is closely related to BRCA1 and can reinforce the important roles of miR-155 in breast cancer development.

In microarray analyses, the miR-155 promoter has been shown to harbour the binding sequence of some transcription factors which were reported changed in breast cancer, such as FOXO3a, PBX1 and Sp1.[39–41] This indicates that the expression level of miR-155 could be considered one of the typical changes in breast cancer.

Target genes of miR-155

The main function of miRNAs is to inhibit their target mRNAs by binding to the 3′UTR of mRNAs and consequently affecting the corresponding cellular processes. Therefore, understanding the role of miR-155 in breast cancer requires the identification of critical miR-155 targets.

Using TargetScan (http://www.targetscan.org/), 440 conserved targets of miR-155 in human genes were identified. Some miR-155 target genes, such as those encoding SOCS1 and FOXO3a, have a confirmed role in breast cancer development. SOCS1 expression is inversely correlated with miR-155 in breast cancer cell lines as well as in a subset of primary breast tumours.[9] Overexpression of miR-155 in breast cancer cells induces the activation of transcription 3 (STAT3) through the Janus-activated kinase pathway, and stimulation of breast cancer cells by the inflammatory cytokines IFN-γ, interleukin-6 and lipopolysaccharide, suggesting that miR-155 may serve as a bridge between inflammation and cancer.[9] FOXO3a is a transcription factor which plays a crucial role in apoptosis and cell growth by regulation of a number of apoptosis/cell growth associated genes, and miR-155 can directly interact with the 3′UTR of FOXO3a and block FOXO3a translation.[19,42,43]

Moreover, a number of target genes of miR-155 are involved in cancer-related pathways such as cell growth and survival (CCND1, GAB3), cell migration and invasion (PAK2, RAB6A), cell adhesion junction (ANKRD6, SMAD2), apoptosis and proliferation.[18,44–46] It is, thus, suggested that miR-155 also affects the development of breast cancer.

Although the knowledge about the expression and function of miR-155 in breast cancer may still be not complete, there appears to be accumulating evidence that miR-155 could be considered a potential therapeutic target and/or, hypothetically, a diagnostic biomarker in breast cancer. Such potential uses of miR-155, however, need further exploration.

Conclusions

The present mini-review attempted to summarize, although perhaps not completely comprehensively, the available data on miR-155 expression and function in breast cancer. MiR-155 has been identified as an oncogenic miRNA. It is involved in the control of several signalling pathways, such as cell growth and survival, cell migration and invasion, cell adhesion junction, apoptosis and proliferation. The role of miR-155 in the regulation of human breast cancer suggests great potential for diagnostic and therapeutic strategies in breast cancer. Moreover, much of the underlying roles of miR-155 in breast cancer are still largely unknown and the topic requires further exploration. Further studies of miRNA targets and functions in breast cancer will be required to uncover the relationship between miRNA regulation and breast cancer mechanisms.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Nature Science Foundation of Yunnan Province [grant number 2013FC006]; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education [grant number 2014016]; Nature Science Foundation of Yunnan Province [grant number KKSY201460043].