Open access peer-reviewed chapter

Duplicitous Dispositions of Micro-RNAs (miRs) in Breast Cancer

Written By

Amal Qattan

Submitted: March 26th, 2019 Reviewed: July 8th, 2019 Published: August 17th, 2019

DOI: 10.5772/intechopen.88466

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In 1993, a gene silencer known as lin-4 was first discovered in Caenorhabditis elegans and demonstrated to be critical for larval development. Lin-4 belongs to a family of signaling molecules known as non-protein coding microRNAs (miRNAs) which are not only highly conserved in humans, but also involved in the fundamental processes of oncogenesis. While miRNAs are not translated to proteins themselves, they are capable of regulating the expression and translation of other genes thus affecting a multitude of biological and pathological pathways as well as those essential to the malignant landscape. The aim of this chapter is to explore the diverse roles of miRNAs in the context of breast cancer. Following a brief overview of miRNA biogenesis, this chapter covers the production of miRNAs by tumor cells and stromal cells, onco-suppressor miRNAs, use as therapeutics, contribution to therapeutic resistance, and finally their emerging role as biomarkers.


  • microRNAs (miRs)
  • breast cancer epigenetic alteration
  • microRNA-based therapy
  • miRNA pharmacogenomics
  • miRSNPs
  • miR-polymorphisms
  • clinical trials

1. Introduction

A gene silencer known as lin-4was first discovered in Caenorhabditis elegansand demonstrated to be critical for larval development [1]. Lin-4belongs to a family of signaling molecules known as non-protein coding microRNA (miRNAs) which are not only highly conserved in humans, but also involved in the fundamental processes of oncogenesis [2]. Approximately 2000 miRNAs are present in the human genome [3]. While miRNAs are not translated into proteins themselves, they are implicated in the regulation of 30% of all genes and are thereby capable of regulating the expression and translation of other genes influencing a multitude of biological and pathological pathways [4]. This chapter explores the diverse roles of miRNAs in the most frequent cancer among women in the world: breast cancer (BC). BC impacts 2.1 million women yearly [5] and it also causes the greatest number of cancer-related deaths among women. Early detection and diagnosis are critical to survival. In the context of BC, miRNAs are dynamically regulated implicating their use in diagnosis, prognosis and tracking of drug efficacy during treatment. Following a brief overview of miRNA biogenesis, this chapter covers the production of miRNAs by tumor cells, onco-suppressor and tumor-suppressor miRNAs, their contribution to therapeutic resistance, therapeutic miRNAs (as well as therapeutics targeting of miRNAs), and finally their emerging role as biomarkers for BC prognosis, treatment responsiveness and efficacy.


2. MiRNA biogenesis and mechanisms of action

Since 1993, researchers have proceeded to learn that miRNAs were of ancient evolutionary origins. Single stranded, non-protein coding miRNAs with genetic suppression activities were found in algae, plants, invertebrates, vertebrates and even viruses [6]. Further characterization has revealed that miRNAs are not only critical for normal human development, but their aberrant expression is associated with diseases such as cancer [7, 8].

The miRNAs are encoded by genetic sequences which may be located within the introns of protein coding genes as well as in the exons and introns of long noncoding RNAs, and even intergenic regions [9]. According to the miRIAD database, 1157 (61.5%) miRNAs are intragenic (169 exonic and 988 intronic) and 724 (38.5%) are intergenic [10]. MiRNA’s are single-stranded RNA transcripts that are transcribed from DNA sequences and are usually around 22 nucleotides in length. They often form distinct secondary folding conformational motifs. Most miRNAs are first transcribed into primary miRNAs (pri-miRNAs) and processed into precursor miRNAs (pre-miRNAs) and mature miRNAs. Usually they bind to the 3′-untranslated region (UTR) of target mRNAs to suppress their target’s expression by inhibiting its translation. However, they can also interact with coding sequences, the 5′UTR and gene promoter regions. Though less common, some are involved in the translation activation and stabilization of target transcripts. Furthermore, the shuttling of miRNAs between different cellular compartments can also control rates of transcription and translation of their targets.

In the canonical pathway of miRNA biogenesis, RNA polymerase II transcribes miRNAs into primary miRNAs (pri-miRNAs) greater than 200 nucleotides long. Pri-mRNAs are then cleaved into pre-mRNAs by the RNAse III enzyme, Drosha with the help of double stranded RNA binding proteins Pasha and DiGeorge Syndrome Critical Region 8 (DGCR8). The 60–70 nucleotides long pre-mRNAs are then exported out of the nucleus and into the cell cytoplasm by exportin-5 and Ran GTPase. Once in the cytoplasm, pre-mRNAs are cleaved by the RNAse III enzyme Dicer which removes hairpin loops resulting in miRNA duplexes composed of a guide strand and a passenger strand. The passenger strand is discarded and the guide strand associates with Argonaute 2 (Ago2) to form the RNA-induced silencing complex (RISC) which brings the miRNA to its target mRNA. A 6–8 nucleotide sequence on the miRNA, referred to as the “seed sequence” locates the corresponding sequence of the target mRNA. A double stranded complex is formed which impedes the ribosome from translating the target [11]. Imperfect complementarity between the seed sequence and the target mRNA can also cause target degradation indirectly via deadenylation at the 3′-UTR. Non-canonical miRNA biogenesis is less common and can generally be grouped into Drosha/DGCR8-independent and Dicer-independent pathways which are outside the scope of this chapter. In addition to the inhibition of target miRNAs, there is evidence indicating that some miRNAs directly increase target translation via recruitment of protein synthesis complexes to the translation initiation region. Alternatively, target mRNA expression can also be increased due to inhibition of modulating repressors that block translation. Moreover, some miRNAs enhance ribosome biogenesis resulting in increased protein synthesis [12].

In summary, miRNA biogenesis is a multi-step process that requires various enzymes and shuttling proteins to reach a final product. Mature miRNAs are either stable molecules with half-lives of greater than 24 h or they display shorter half-lives of less than 12 h, depending on the functionality of the product [13]. More on the regulation of miRNA expression is discussed in the next section.


3. Regulation of miRNA expression

In general, just as protein-coding genes are regulated by transcription factors (TF), TFs are one of the central ways by which miRNA expression is regulated. Tissue and developmental stage specific TFs can control the transcription of miRNA genes. Many miRNAs and TFs form autoregulatory loops, in which they mutually regulate each other [14]. In addition, various physiological and pathological stimuli, such as steroid hormones, retinoids, hypoxia, interferons, stress, as well as estrogen, can affect miRNA expression [15]. Finally, while transcription regulates the magnitude of miRNA expression, decay rates influence miRNA dynamic regulation. Slow decay leads to a high level of accumulation while fast decay leads quick changes in miRNA expression levels implying that fast turnover may be involved in transient biological processes.

Epigenetic mechanisms are heritable changes in gene expression that occur without any modifications in the DNA sequence itself and include DNA methylation and histone modifications as well as miRNAs themselves [16]. The covalent binding of methyl groups to cytosine bases located among CpG dinucleotide sequences is the major modification of eukaryotic genomes which results in down regulation of gene expression. DNA methylation controls embryonic cell fate lineages and prevents reversion to an undifferentiated state [17]. Frequency of methylation is nearly one order of magnitude higher in human miRNA genes compared to the methylation of other protein-coding genes [18, 19]. This indicates strict epigenetic control of miRNA expression and also reveals how epigenetic changes in cancer cells can lead to dysregulated expression of miRNAs by cancer cells.

Genome variations include genetic mutations and polymorphisms; defined as a DNA variation in which a possible sequence is present in at least 1% of people. Single nucleotide polymorphisms (SNPs) constitute approximately 1% of the human genome. SNPs contribute to phenotypic diversity within a species as well as disease susceptibility. MiRSNPs/miR-polymorphisms are a new mechanism and novel class of functional SNPs. As miRNA molecular interactions with their targets are affected via base pairing as well as genetic variation, such as changes in genome sequence; which influences binding energy and annealing strength, SNPs can result in no change, off target or absence of miRNA binding to the predicted target [20]. Carcinogens such as those from cigarettes, dietary elements and other foreign chemical toxicities referred to as “xenobiotics,” can also affect miRNA expression. Importantly, many more changes in miRNA expression were observed in cancer-target tissues than in the non-target tissues following acute or chronic exposure to carcinogens thus implicating their use as potential biomarkers for exposure to xenobiotics [21]. Finally, circadian rhythm control of miRNA expression has significant consequences for circadian timing as some miRNAs have promoter sequences inducible by circadian clock proteins. Moreover, some miRNAs can even be regulated by light and dark cycles which confer important rhythmic expressions in organs such as the liver and heart [22].

In summary, miRNA regulation is similar to other protein coding gene regulation as changes in expression can occur based on the presences or exposure to TFs, genetic polymorphisms, epigenetic factors, xenobiotics and carcinogens. How miRNA expression is regulated in the context of BC is discussed in the next section.


4. miRNAs (miRs) production by breast cancer cells

As summarized above, TF, SNPs, epigenetics, hormones and xenobiotics all affect the regulation of miRNAs; therefore, it is not surprising that breast cancer (BC) leads to significant, dynamic changes in miRNA expression both by tumor cells and by surrounding stromal cells. This section describes BC tumor cell production of miRNAs as well as the surrounding non-cancerous stromal cells. In general, miRNAs either support or suppress tumorigenesis and are often dysregulated due to tumor-specific epigenetic changes. Likewise, tumor secreted factors such as exosomes and cytokines can also lead to aberrant signaling in the surrounding stromal cells. Furthermore, while all BCs begin in the breast, there are many subtypes which are named to reflect their particular molecular pathogenesis. Subtype diagnosis can help select appropriate therapies. Likewise, aberrant regulation of miRNAs can be subtype specific. Therefore, this section begins with a brief overview of cancer subtypes.

Breast carcinoma can begin either in the ducts or the lobules and as such, termed either ductal carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS). Both can either stay contained to the area or travel to surrounding tissue and lymph nodes in which case the clinical diagnosis is either invasive ductal carcinoma (IDC) or invasive lobular carcinoma (ILC). IDC is the most common type of BC (50–75%) followed by ILC (5–15%) [23]. Rare BC is characterized by tumor origination in the mucinous, papillary, medullary or cribriform compartments of the breast [24]. Metastasis of breast cancer to other organs is the main cause of mortality and up to 5% of patients will already have experienced metastasis at the time of diagnosis [25].

MiRNA microarray performed on 1542 breast tissue samples procured via the Molecular Taxonomy of Breast Cancer International Consortium and the Akershus University Hospital (AHUS) revealed that no miRNAs were differentially expressed in DCIS patients relative to IDC, supporting the idea that miRNA dysregulation occurs at an early stage of BC development [26]. Among the invasive subtypes, however, expression of seven miRNAs was consistently downregulated, including tumor suppressors let-7c-5p, miR-125b-5p, miR140-3p, miR-145-3p, miR-145-5p, miR-193a-5p, and miR378a-3p while expression of four oncogenic miRNAs was consistently upregulated including miR-106b-5p, miR-142, miR-342-3p, and miR425-5p. Taken together these miRNAs may significantly contribute to the transition to an invasive BC subtype [26].

While Bloom and Richardson’s histologic grading system which was modified by Elston and Ellis in 1991 is the most commonly used system to gain prognostic insight, hormone receptors status, tumor size, nodal status and whether tumorous cells have invaded the lymph or blood vessels is also considered during initial diagnosis. Hormone receptor statuses including estrogen receptor (ER) and progesterone receptor (PR) as well as the tyrosine kinase receptor, human epidermal growth receptor type two (HER2) are always measured on newly diagnosed invasive BCs. Subtypes are identified via immunohistochemical staining for hormone receptors, HER2 expression status, and Ki-67 proliferation index as: luminal A (ER-positive and/or PR-positive, HER2-negative, low proliferation), luminal B (ER-positive and/or PR-positive, HER2-negative, high proliferation; or hormone receptor (HR)-positive and HER2-positive), HER2-positive (HR-negative and HER2-positive) and finally TNBC type (HR-negative and HER2-negative) [27]. ER+ breast cancer subtype is particularly prevalent in postmenopausal women taking hormone replacement therapy (HRT) which activates the transcription factor estrogen receptor alpha (ERα) which promotes the expression of numerous oncogenic genes. While ERα-signaling is targeted by miRNAs for degradation, aberrant activation of this receptor leads to aberrant expression of miRNAs controlled by ERα-signaling [28].

Several miRNAs are both tissue and cancer specific. As the primary role of miRNA is to decrease target mRNA expression, miRNAs that are upregulated by cancerous cells are often those that support cancer growth and are referred to as oncomiRs. miR-10b, miR-21 and miR-155 are well characterized oncomiRs in BC [29]. Their main role is to downregulate tumor suppressor genes which results in the promotion of cancer cell proliferation, de-differentiation and invasion [30]. BC cells also produce less tumor-suppressor miRNAs (miR-31, miR-125b, miR-200 and miR-205) which downregulate oncogenic proteins. Cancer-initiating cells (CSCs) were first isolated from breast cancer tumors and are considered the seed-cells of tumor development [31]. While CSCs are similar to normal somatic stem cells in that they are capable of asymmetric cell division and the efflux of small molecules, they have more phenotypic plasticity. The family of miRNAs known as let-7 was demonstrated to be a master regulator of self-renewal and tumor-seeding ability [32]. Likewise, the process of epithelial to mesenchymal transition (EMT) which enables tumorigenicity and invasion, was facilitated via transforming growth factor β2 (TGF-β2) and Zeb1 transcription factor mediated repression of the miR-200 and miR-141; two miRNAs which are responsible for epithelial differentiation [33].

In summary, reflecting the cancer cells aim of aberrant, dysregulated gene expression needed for tumor cell survival and proliferation, a global downregulation of all miRNAs is observed in cancer. In tumor cells, the main mechanism by which global miRNA production is suppressed is via the upregulation of miRNAs that target the crucial miRNA biogenesis enzyme Dicer, miR-103 and miR-107 [34]. Likewise, chromatin remodeling that results in an increase in miRNAs that support EMT and self-renewal rather than continuation of a differentiated cell type is observed [35].


5. miRNAs affecting breast cancer chemotherapy efficacy and resistance

Chemoresistance is the primary cause of treatment failure in breast cancer. Dysregulation of some miRNAs can result in increases in drug efflux, alter drug targets and energy metabolism, stimulate DNA repair pathways and evasion of apoptosis and result in loss of cell cycle control. The first BC drug was a DNA-replication blocker called doxorubicin. Resistance to doxorubicin correlated with downregulation of miR-505, miR-128, and miR-145 tumor suppressors [36, 37, 38, 39, 40, 41]. In contrast, miR-663, miR-181a, and miR-106b are oncogenic miRNAs whose downregulation resulted in enhancement of doxorubicin sensitivity in formerly resistant cells [41, 42, 43]. Like doxorubicin, cisplatin inhibits DNA replication and was also one of the first established therapies for BC. Upregulation of miR-345 and miR-7 contribute to cisplatin-resistance, while miR-302b can sensitize resistant cells to cisplatin therapy [44, 45]. A list of miRNA expression levels and targets of BC drug resistant is listed in Table 1.

miRNABC therapyTargetsLevelMechanism/Refs.
miR-200CarboplatinZebReverses EMT [46]
miR-345CisplatinMRP1Not yet characterized [45]
miR-302bCisplatinE2F1 (direct)Inhibit cell cycle progression [44]
ATM (indirect)
miR-24CisplatinBimL F1H1Promotes EMT and cancer stem cells [47]
miR-106b~25 clusterDoxorubicinEP300Activates EMT [43]
miR-128DoxorubicinBmi-1 ABCC5Increases apoptosis [48]
miR-145DoxorubicinMRP1Induces intracellular doxorubicin accumulation [36]
miR-181aDoxorubicinBcl-2Increases apoptosis [41]
miR-181aDoxorubicinBaxInhibits apoptosis [49]
miR-25DoxorubicinULK1Inhibits autophagy [50]
miR-326DoxorubicinMDR-1Downregulates MRP-1 [51]
miR-505DoxorubicinAkt3 (indirect)Not yet investigated [37]
miR-644aDoxorubicinCTBP1Inhibits EMT [52]
miR-663DoxorubicinHSPG2Inhibits apoptosis [42]
miR-129-3pDocetaxelCP100Reduces cell cycle arrest and apoptosis [53]
miR-34aDocetaxelBCL-2 CCND1Inhibit apoptosis [54]
miR-484GemcitabineCDAPromote proliferation and cell-cycle redistribution [55]
miR-218MDRSurvivinEnhance apoptosis [56]
miR-100PaclitaxelmTOREnhance cell cycle arrest and apoptosis [57]
miR-125bPaclitaxelSema4CReverses EMT [58]
miR-125bTaxolBak1Inhibits apoptosis [59]
miR-30cDoxorubicinTWF1 (PTK9) VIM IL-11Reverses EMT [60]
miR-34aDoxorubicinHDAC1HDAC7Inhibits autophagic cell death [61]

Table 1.

miRNAs involved in the regulation of common breast cancer drugs.

Abbreviations: Expression level of miRs: upregulation (↑) or downregulation (↓) of miRNAs in breast cancer therapy. The reference of each miR is included in the table. Table adapted from Hu et al. [62].

In addition to doxorubicin and cisplatin, efficacy of the chemotherapeutic agents docetaxel and paclitaxel which inhibit microtubule formation during cell division, can also be compromised by miRNAs. Downregulation of miR-34a, miR-100, and miR-30c were observed in paclitaxel-resistant BC cell while the upregulation of miR-129-3p was found to contribute to resistance [57, 58, 59, 60, 61].

In ER+ breast cancer, de novoand acquired resistance to conventional endocrine therapies such as aromatase inhibitors, fulvestrant and tamoxifen, can occur in more than 30% of patients [63]. Evidence suggests that resistance to these drugs is in part mediated by miRNAs. As most BC patients have high estrogen receptor-α (ER-α) expression, targeting ER-α signaling is a critical therapy. Resistance to tamoxifen, an agent which blocks interaction between estrogen and estrogen receptor is associated with the downregulation of the following tumor suppressor miRNAs: miR-15a, miR-16, miR-214, miR-320, miR-342, miR-451, miR-873, miRNA-375, miR-378a-3p, and miR-574-3p [64, 65, 66, 67, 68, 69, 70, 71] .In contrast, oncogenic miRs: miR-101, miR-221/222, miR-301, and miRNAs-C19MC were highly expressed in tamoxifen resistant cells [72, 73, 74, 75]. In addition, both the humanized monoclonal antibody targeting HER2 named trastuzumab, as well as lapatinib, which is a small-molecule tyrosine kinase inhibitor targeting both HER2 and epithelial growth factor receptor (EGFR), improve therapeutic outcome but result in resistance after 1 year. Resistance to these two drugs is correlated with an upregulation of miR-21, miR-221 and miR-375 [76, 77, 78, 79, 80].

The role of miRNA in chemotherapeutic resistance is associated with the modification of drug transporters which has a net effect of drug efflux out of the cell via exosomes as well as modifications of autophagy and apoptosis pathways which lead to enhanced survival, the promotion of growth factors and activation EMT [81]. The tumor microenvironment which consists of the surrounding stromal cells serve as the normal foundation upon which the deviant tumor “house” is constructed supplying it with blood vessels, signaling molecules and ECM. Exosomes transport bioactive molecules and mediate cellular communication in the tumor microenvironment, facilitating a more cancerous and recalcitrant milieu [82]. For example, exosome-derived miRNAs such as miR-222 transfer doxorubicin-resistance by inhibiting PTEN in recipient cells, 22 miRNAs were concentrated in exosomes and correlated to chemotherapy resistance [83]. While the major function of exosomes in the context of BC and drug resistance is the shuttling of drugs out of the tumor, exosomes can also be bio-hacked for use as a prime chemotherapy delivery system [84, 85, 86].

In summary, in the context of breast cancer, tumor cells regulate miRNAs in a way that promotes tumor survival, growth and invasion. Aside from a global downregulation of most miRNAs and especially tumor suppressor miRNAs, oncogenic miRNAs are increased and often exported via exosomes where they are taken up by non-cancerous cells, transforming the local environment to a pro-cancer milieu. Knowing how BC cells regulate miRNAs opens the door for potential therapies that target oncogenic miRNAs (antagomirs) or add back tumor suppresser miRNAs (mimic miRNAs). The targeting of miRs in breast cancer is discussed in the following section.


6. miRNAs as breast cancer therapy

As reviewed in this chapter, miRNAs are dynamically regulated in BC and can also contribute to drug resistance. Therefore, interventions that disrupt activities of dysregulated miRNAs offer promising targets for novel therapeutics in the form of mimics or antagomirs. In addition, mature miRNAs and their precursors can also be targeted by small molecules. In general, there are two strategies for targeting miRNA in BC. In the first strategy, tumor suppressor miRNAs which are down regulated by tumor cells can be added back to the tumor microenvironment using chemically synthesized miRNA mimics which imitate endogenous mature double-stranded miRNA [87]. MiRNA mimics could be delivered in viral vectors which would allow extended expression. The second strategy is to target oncogenic miRNAs which are highly expressed and exported by tumor cells. In this strategy, oligonucleotides, locked-nucleic-acids antisense oligonucleotides (LNAs), miRNA sponges, multiple-target anti-miRNA antisense oligo-deoxyribonucleotides (MTg-AMOs), miRNA-masking and nanoparticles are used to target for degradation or impede aberrantly expressed oncogenic miRNAs from reaching their targets [88, 89, 90, 91].

As previously mentioned, the majority of highly expressed, dysregulated miRNAs in tumor cells are oncomirs, or those that support tumorigenesis, while tumor suppressor miRNAs are suppressed [92]. For example, miR-155 is an oncogenic miRNA upregulated in BC tumor tissue. Targeting of miR-155 with an antisense oligonucleotide (miR-155) in a BC cell line blocked proliferation and augmented apoptosis [93]. MiR-892b is an example of a tumor suppressor miRNA that is significantly downregulated in BC tissue specimens. By supplementing miR-892b “mimics” in BC cells, a decrease in tumor growth, metastases rate, and angiogenesis was observed. MiR-892b mimic blocked impeded tumorigenesis by attenuating nuclear transcription factor kappa B (NF-kB) signaling [94]. Artificial miRNAs can also be constructed to inhibit targets that are not normally targeted by endogenous miRNAs. For example, a novel artificial miRNA (amiRNA) called miR-p-27-5p, which targets the 3′-UTR of cyclin-dependent kinase 4 (CDK4) mRNA, inhibited cell cycle progression via downregulation of CDK4 expression and suppression of retinoblastoma protein (RB1) phosphorylation [95]. Likewise, an a miRNA against a C-X-C motif chemokine receptor 4 (CXCR4) inserted into an expression vector reduced CXCR4 expression and suppressed migration and invasion of BC cells [96]. While in vitro experiments provide proof of concept for further development of miRNA targeting in oncogenic diseases, only clinical trial results can determine whether miRNA therapy is truly efficacious. Patents, clinical trials and biopharmaceutical companies invested in the development of miRNA therapies are summarized by Chakraborty et al, [97]. A seminal trial for miRNA replacement therapy took place employing the tumor suppressor miR-34 mimic (MRX34). MRX34 was formulated for intravenous injection using a liposome delivery system for patients with metastatic liver cancer. MRX34 along with dexamethasone was associated with safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors [98]. However, there were adverse events in the trial which indicate the need for alternative approaches in formulation design and delivery.

In summary, there is much research to be done in the emerging field of miRNA therapeutics. Drug developers, pharmacists, physicians and molecular biologists must work together to develop novel strategies for miRNA delivery that is more targeted and controlled in order to mitigate off-target effects by affecting only cell signaling of targeted tumor cells.


7. miRNAs as breast cancer biomarkers

MiRNAs that maintain a stable presence in the serum are referred to as “circulating” miRNAs. Thus, in addition to therapeutic targeting, many studies have reported utility of miRNAs in the context of BC as biomarkers for diagnostic, prognostic, or predictive of drug efficacy. In this final section, miRNAs currently being used as biomarkers in the context of BC are discussed.

In the context of diagnostics, the current gold standard for BC is mammography. However, many women avoid mammograms for fear of pain or inconvenience in scheduling thus rendering assays performed on less invasive, routine blood draws amenable to early screening for BC. Global profiling of circulating miRNAs in early-stage ER+ BC (n = 48) and age-matched healthy controls (n = 24) revealed a panel of nine miRNAs (miR-15a, miR-18a, miR-107, miR-133a, miR-139-5p, miR-143, miR-145, miR-365 and miR-425) that discriminated between patients with early-stage ER+ BC and healthy controls [99]. A study in Japan performed on serum (n = 1280 BC, n = 2836 non-cancer controls) found a combination of five miRNAs: miR-1246, miR-1307-3p, miR-4634, miR-6861-5p and miR-6875-5p, could predict breast cancer with a sensitivity of 97.3% overall, 98% sensitivity for early stage BC and a specificity of 82.9% and accuracy of 89.7% [100]. A study based in Prague (n = 63 early stage BC, n = 21 non cancer controls) found that several oncogenic miRNAs were significantly elevated in early stage BC; including: miR-155, miR-19a, miR-181b, and miR-24 and unsurprisingly, their expression dropped following surgical resection of the tumor [101]. A study in Singapore performed global profiling of miRNA expression in BC tumor tissue, non-tumor tissue and serum samples obtained from BC patients (n = 132) and from healthy controls (n = 123) revealed miR-1, miR-92a, miR-133a and miR-133b as significantly upregulated diagnostic markers in BC sera [102]. In addition to upregulation of oncogenic miRNAs, tumor suppressor Let-7c was decreased in BC tissue and sera according to a study performed in China (n = 90 BC, n = 64 controls) [103]. Although some studies have suggested that let-7 and miR-195 restoration may be therapeutic, results of Qattan et al. in 2017 [104] supported literature indicating that tumor cells export hsa-miR-195 and let-7 miRNAs. While the data of this study did not generally support the use of these miRNAs as therapies, it suggested that these markers may be the most robust markers to use in a blood-based screen for the early detection of TNBC and luminal breast cancer [104].

The definition of a prognostic biomarker is one that indicates recurrence or progression; such as chance of survival, independent of the course of therapy. In a study based in Germany, pre-operative serum (n = 102) and post-operative serum (n = 34) of BC patients was compared to healthy women (n = 37) or those with benign breast disease (n = 26). The mean follow-up time of for BC patients was 6.2 years. In this study, high expression of miR-202 positively correlated with reduced overall survival (poor prognosis). In a European study, genome-wide miRNA expression profiling using serum from TNBC patients (n = 130) and healthy controls (n = 30), revealed a four-miRNA signature (miR-18b, miR-103, miR-107 and miR-652) that predicted tumor recurrence and overall survival [105]. While few studies have investigated the use of miRNA serum expression levels as a predictive metric for treatment response, clinically relevant outcomes were revealed in the studies performed indicating the need for incentivizing investigations into miRNA biomarkers. For example, elevated miR-125b expression predicts poor prognosis, is associated with tumor size and TNM stage in HER2+ BC as well as poor responsiveness to paclitaxel-based neoadjuvant chemotherapy [106]. Therefore, miR-125b may be a potential predictor of clinical outcome, particularly in HER2+ BC patients receiving paclitaxel-based neoadjuvant chemotherapy. In another example, miR-155 was significantly increased in BC patients (n  =  103) compared with healthy normal (n  =  55). Post-surgical resection and four cycles of chemotherapy, a subset of BC patient sera (n  =  29) were collected to evaluate the effects of clinical treatment on serum levels of candidate miRNAs. Decreased levels of circulating miR-155 post-treatment was associated with response to therapy and stable disease [107].

In summary, the data from these studies and others suggest that BC patients with novel miRNA signatures correlating with poor prognosis are not receiving adequate treatment and should be selected for inclusion in novel randomized clinical trials for the chance to receive alternative life-saving therapies. Table 2 summarizes studies revealing statistically significant regulation of circulating miRNAs with diagnostic (DX), prognostic (PX), predictive biomarkers (PR) potential for BC. Some studies were validated (VA) with alternative cohorts.

BloodmiR-195, let-7 and -155↑ in BC [108]YNNN
SerummiR-214Indicates malignant from benign and healthy [109]YNNN
PlasmamiR-127-3p, -376a, -148b, -409-3p, -652 and -801↑ in BC [110]YNNY
PlasmamiR-148b, -133a, and -409-3p↑ in BC [111]YNNY
SerummiR-15a↑ in BC [99]YNNY
miR-18a, -107, -425, -133a, -139-5p, -143, -145, and -365↓ in BC [99]
SerummiR-484↑ in BC [112]YNNY
SerummiR-1246, -1307-3p, and -6861-5p↑ in BC [100]YNNY
miR-4634 and -6875-5p↓ in BC [100]
SerummiR-155, -19a, -181b, and -24↑ in BC [101]YNNN
SerummiR-1, -92a, -133a, and -133b↑ in BC [102]YNNY
PlasmamiR-505-5p, -125b-5p, -21-5p, and -96-5p↑ in BC [113]YNNY
Serumlet-7c↓ in BC [103]YNNN
SerummiR-182↑ in BC [114]YNNN
BloodmiR-138↑ in BC [115]YNNN
SerummiR-155Correlates w/PR status [116]YNNN
SerummiR-21, -126, -155, -199a, and -335Associated w/histological tumor grade and sex hormone receptor expression [117]YNNN
Serum; PlasmamiR-4270, -1225-5p, -188-5p, -1202, -4281, -1207-5p, -642b-3p, -1290, and -3141↑ in BC and correlates w/stage and molecular subtype [118]YNNY
SerummiR-202 and let-7b↑ expression in BC and correlates w/tumor aggressive and overall survival [119]YYNN
SerummiR-148b-3p and -652-3p↓ in the BC [120]YYNY
miR-10b-5p↑ levels correlate w/poor prognosis [120]
SerummiR-18b, -103, -107, and -652Associated w/tumor relapse and overall survival in TNBC [105]YYNY
PlasmamiR-10b and -373↑ in breast cancer w/LN metastasis [121]YYNY
SerummiR-10b, 34a, and -155Correlates w/tumor stage and/or metastasis [122]YYNN
SerummiR-29b-2, miR-155, miR -197 and miR -205Correlates w/tumor grade and metastasis [123]YYNN
SerummiR-92a↓ in BC, LN metastasis [124]YYNN
miR-21↑ in BC, LN metastasis [124]
SerummiR-21-5p, -375, -205-5p, and -194-5p↑ in recurrent BC [125]YYNY
miR-382-5p, -376c-3p, and -411-5p↓ in recurrent BC [125]
SerummiR-34a, -93, -373, -17, and -155Expression correlated w/metastasis and HER2, PR, and ER status [126]YNNN
SerummiR-125b↑ expression in non-responsive [127]YNYN
SerummiR-122↓ in NR and pCR [128]NNYY
miR-375↑ in NR and pCR [128]
SerummiR-155↑ in BC; ↓ post chemo [107]YNYN

Table 2.

Circulating miRNAs; diagnostic, prognostic, predictive and validated biomarkers in breast cancer.

Abbreviations: DX, diagnostic; PX, prognostic; PR, predictive; VA, validated; BC, breast cancer; ddPCR, droplet digital PCR; DS, deep sequencing; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LN, lymph node; miRNA (miR), microRNA; PR, progesterone receptor; qRT-PCR, quantitative reverse transcriptase real-time PCR; TNBC, triple-negative breast cancer; NR, non-relapse; pCR, Pathologic complete response.


8. Conclusions

In conclusion, this chapter provided an overview of the most recent studies describing the dynamic roles of miRNAs in the context of BC. This overview demonstrates that just as miRNAs are integral to maintaining normal homeostasis, they are simultaneously sensitive to changes in overall physiology and local micro-environments thus studying them will likely lead to insight into the unique manifestation of BC in an individual. Given that they are actively released by tumor cells into the circulatory system, both monitoring and targeting miRNAs enables the diagnosis and monitoring of BC as well as the opportunity for the development of novel therapeutics. Future studies should employ well standardized methods for sample collection and multi-center global miRNA profiling to reveal novel nuances and robust results regarding miRNA signaling in the context of BC. Taken together, the emerging field of precision oncology may rely on understanding miRNA profiles.


  1. 1. Lee RC, Feinbaum RL, Ambros V. TheC. elegansheterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843-854
  2. 2. Barbato S, Solaini G, Fabbri M. MicroRNAs in oncogenesis and tumor suppression. In: International Review of Cell and Molecular Biology. Galluzzi L, Vitale I, editors. MiRNAs in Differentiation and Development. Elsevier. 2017;333:229-268. DOI: 10.1016/bs.ircmb.2017.05.001. ISBN: 978-0-12-811870-2
  3. 3. Kawahara Y. Human diseases caused by germline and somatic abnormalities in microRNA and microRNA-related genes. Congenital Anomalies (Kyoto). 2014;54:12-21. DOI: 10.1111/cga.12043
  4. 4. Schmidt MF. Drug target miRNAs: Chances and challenges. Trends in Biotechnology. 2014;32:578-585. DOI: 10.1016/j.tibtech.2014.09.002
  5. 5. WHO. Breast cancer. 2018. Available from:
  6. 6. Moran Y, Agron M, Praher D, Technau U. The evolutionary origin of plant and animal microRNAs. Nature Ecology and Evolution. 2017;1:0027. DOI: 10.1038/s41559-016-0027
  7. 7. Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005;132:4653-4662. DOI: 10.1242/dev.02073
  8. 8. Lin Y, Zeng Y, Zhang F, Xue L, Huang Z, Li W, et al. Characterization of microRNA expression profiles and the discovery of novel microRNAs involved in cancer during human embryonic development. PLoS One. 2013;8:1-11. DOI: 10.1371/JOURNAL.PONE.0069230
  9. 9. Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Research. 2004;14:1902-1910. DOI: 10.1101/gr.2722704
  10. 10. Hinske LC, França GS, Torres HAM, Ohara DT, Lopes-Ramos CM, Heyn J, et al. miRIAD—Integrating microRNA inter- and intragenic data. Database. 2014;2014:1-9. DOI: 10.1093/database/bau099
  11. 11. Ha M, Kim VN. Regulation of microRNA biogenesis. Nature Reviews. Molecular Cell Biology. 2014;15:509-524. DOI: 10.1038/nrm3838
  12. 12. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: MicroRNAs can up-regulate translation. Science (80-). 2007;318:1931-1934. DOI: 10.1126/science.1149460
  13. 13. Rüegger S, Großhans H. MicroRNA turnover: When, how, and why. Trends in Biochemical Sciences. 2012;37:436-446. DOI: 10.1016/j.tibs.2012.07.002
  14. 14. Tsang J, Zhu J, van Oudenaarden A. MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Molecular Cell. 2007;26:753-767. DOI: 10.1016/j.molcel.2007.05.018
  15. 15. Gulyaeva LF, Kushlinskiy NE. Regulatory mechanisms of microRNA expression. Journal of Translational Medicine. 2016;14:143. DOI: 10.1186/s12967-016-0893-x
  16. 16. Goldberg AD, Allis CD, Bernstein E. Epigenetics: A landscape takes shape. Cell. 2007;128:635-638. DOI: 10.1016/j.cell.2007.02.006
  17. 17. Messerschmidt DM, Knowles BB, Solter D. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes & Development. 2014;28:812-828. DOI: 10.1101/gad.234294.113
  18. 18. Weber B, Stresemann C, Brueckner B, Lyko F. Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle. 2007;6:1001-1005. DOI: 10.4161/cc.6.9.4209
  19. 19. Morales S, Monzo M, Navarro A. Short conceptual overview epigenetic regulation mechanisms of microRNA expression. Biomolecular Concepts. 2017;8:203-212. DOI: 10.1515/bmc-2017-0024
  20. 20. Wilk G, Braun R. regQTLs: Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors. PLoS Genetics. 2018;14:e1007837. DOI: 10.1371/journal.pgen.1007837
  21. 21. CHEN T. The role of MicroRNA in chemical carcinogenesis. Journal of Environmental Science and Health, Part C. 2010;28:89-124. DOI: 10.1080/10590501.2010.481477
  22. 22. Hansen KF, Sakamoto K, Obrietan K. MicroRNAs: A potential interface between the circadian clock and human health. Genome Medicine. 2011;3:10. DOI: 10.1186/gm224
  23. 23. Cruz-Roa A, Gilmore H, Basavanhally A, Feldman M, Ganesan S, Shih NNC, et al. Accurate and reproducible invasive breast cancer detection in whole-slide images: A deep learning approach for quantifying tumor extent. Scientific Reports. 2017;7:46450. DOI: 10.1038/srep46450
  24. 24. Russnes HG, Lingjærde OC, Børresen-Dale A-L, Caldas C. Breast cancer molecular stratification. The American Journal of Pathology. 2017;187:2152-2162. DOI: 10.1016/j.ajpath.2017.04.022
  25. 25. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: A Cancer Journal for Clinicians. 2011;61:69-90. DOI: 10.3322/caac.20107
  26. 26. Tahiri A, Leivonen S-K, Lüders T, Steinfeld I, Ragle Aure M, Geisler J, et al. Deregulation of cancer-related miRNAs is a common event in both benign and malignant human breast tumors. Carcinogenesis. 2014;35:76-85. DOI: 10.1093/carcin/bgt333
  27. 27. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Panel members: Tailoring therapies—Improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer 2015. Annals of Oncology. 2015;26:1533-1546. DOI: 10.1093/annonc/mdv221
  28. 28. Howard EW, Yang X. microRNA regulation in estrogen receptor-positive breast cancer and endocrine therapy. Biological Procedures Onlin. 2018;20:17. DOI: 10.1186/s12575-018-0082-9
  29. 29. Hemmatzadeh M, Mohammadi H, Jadidi-Niaragh F, Asghari F, Yousefi M. The role of oncomirs in the pathogenesis and treatment of breast cancer. Biomedicine & Pharmacotherapy. 2016;78:129-139. DOI: 10.1016/j.biopha.2016.01.026
  30. 30. Wang W, Luo Y. MicroRNAs in breast cancer: Oncogene and tumor suppressors with clinical potential. Journal of Zhejiang University. Science. B. 2015;16:18-31. DOI: 10.1631/jzus.B1400184
  31. 31. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences. 2003;100:3983-3988. DOI: 10.1073/pnas.0530291100
  32. 32. Yu F, Yao H, Zhu P, Zhang X, Pan Q , Gong C, et al. Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131:1109-1123. DOI: 10.1016/J.CELL.2007.10.054
  33. 33. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Reports. 2008;9:582-589. DOI: 10.1038/embor.2008.74
  34. 34. Martello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, et al. A microRNA targeting dicer for metastasis control. Cell. 2010;141:1195-1207. DOI: 10.1016/j.cell.2010.05.017
  35. 35. Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell. 2013;154:311-324. DOI: 10.1016/j.cell.2013.06.026
  36. 36. Gao M, Miao L, Liu M, Li C, Yu C, Yan H, et al. miR-145 sensitizes breast cancer to doxorubicin by targeting multidrug resistance-associated protein-1. Oncotarget. 2016;7:59714-59726. DOI: 10.18632/oncotarget.10845
  37. 37. Yamamoto Y, Yoshioka Y, Minoura K, Takahashi R, Takeshita F, Taya T, et al. An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells. Molecular Cancer. 2011;10:135. DOI: 10.1186/1476-4598-10-135
  38. 38. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nature Reviews. Cancer. 2002;2:489-501. DOI: 10.1038/nrc839
  39. 39. Yuan X-J, Whang YE. PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway. Oncogene. 2002;21:319-327. DOI: 10.1038/sj.onc.1205054
  40. 40. Wan X, Yokoyama Y, Shinohara A, Takahashi Y, Tamaya T. PTEN augments staurosporine-induced apoptosis in PTEN-null Ishikawa cells by downregulating PI3K/Akt signaling pathway. Cell Death and Differentiation. 2002;9:414-420. DOI: 10.1038/sj/cdd/4400982
  41. 41. Zhu Y, Wu J, Li S, Ma R, Cao H, Ji M, et al. The function role of miR-181a in Chemosensitivity to Adriamycin by targeting Bcl-2 in low-invasive breast cancer cells. Cellular Physiology and Biochemistry. 2013;32:1225-1237. DOI: 10.1159/000354521
  42. 42. Hu H, Li S, Cui X, Lv X, Jiao Y, Yu F, et al. The overexpression of hypomethylated miR-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (HSPG2). The Journal of Biological Chemistry. 2013;288:10973-10985. DOI: 10.1074/jbc.M112.434340
  43. 43. Zhou Y, Hu Y, Yang M, Jat P, Li K, Lombardo Y, et al. The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300. Cell Death and Differentiation. 2014;21:462-474. DOI: 10.1038/cdd.2013.167
  44. 44. Cataldo A, Cheung DG, Balsari A, Tagliabue E, Coppola V, Iorio MV, et al. miR-302b enhances breast cancer cell sensitivity to cisplatin by regulating E2F1 and the cellular DNA damage response. Oncotarget. 2016;7:786-797. DOI: 10.18632/oncotarget.6381
  45. 45. Pogribny IP, Filkowski JN, Tryndyak VP, Golubov A, Shpyleva SI, Kovalchuk O. Alterations of microRNAs and their targets are associated with acquired resistance of MCF-7 breast cancer cells to cisplatin. International Journal of Cancer. 2010;127:1785-1794. DOI: 10.1002/ijc.25191
  46. 46. Nurse P. Cyclin dependent kinases and cell cycle control (Nobel Lecture) Copyright © The Nobel Foundation, 2002. We thank the Nobel foundation, Stockholm, for permission to print this lecture. Chembiochem. 2002;3:596. DOI: 10.1002/1439-7633(20020703)3:7<596::AID-CBIC596>3.0.CO;2-U
  47. 47. Bai W-D, Ye X-M, Zhang M-Y, Zhu H-Y, Xi W-J, Huang X, et al. MiR-200c suppresses TGF-β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer. International Journal of Cancer. 2014;135:1356-1368. DOI: 10.1002/ijc.28782
  48. 48. Zhu Y, Yu F, Jiao Y, Feng J, Tang W, Yao H, et al. Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5. Clinical Cancer Research. 2011;17:7105-7115. DOI: 10.1158/1078-0432.CCR-11-0071
  49. 49. Clarke R, Skaar TC, Bouker KB, Davis N, Lee YR, Welch JN, et al. Molecular and pharmacological aspects of antiestrogen resistance. The Journal of Steroid Biochemistry and Molecular Biology. 2001;76:71-84
  50. 50. Wang Z, Wang N, Liu P, Chen Q , Situ H, Xie T, et al. MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin. Oncotarget. 2014;5:7013-7026. DOI: 10.18632/oncotarget.2192
  51. 51. Liang Z, Wu H, Xia J, Li Y, Zhang Y, Huang K, et al. Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochemical Pharmacology. 2010;79:817-824. DOI: 10.1016/j.bcp.2009.10.017
  52. 52. Reed JC. Bcl-2 family proteins. Oncogene. 1998;17:3225-3236. DOI: 10.1038/sj.onc.1202591
  53. 53. Zhang Y, Wang Y, Wei Y, Li M, Yu S, Ye M, et al. MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition. Scientific Reports. 2015;5:15424. DOI: 10.1038/srep15424
  54. 54. Li L, Yuan L, Luo J, Gao J, Guo J, Xie X. MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clinical and Experimental Medicine. 2013;13:109-117. DOI: 10.1007/s10238-012-0186-5
  55. 55. Ye F-G, Song C-G, Cao Z-G, Xia C, Chen D-N, Chen L, et al. Cytidine deaminase axis modulated by miR-484 differentially regulates cell proliferation and Chemoresistance in breast cancer. Cancer Research. 2015;75:1504-1515. DOI: 10.1158/0008-5472.CAN-14-2341
  56. 56. Hu Y, Xu K, Yagüe E. miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer. Breast Cancer Research and Treatment. 2015;151:269-280. DOI: 10.1007/s10549-015-3372-9
  57. 57. Zhang B, Zhao R, He Y, Fu X, Fu L, Zhu Z, et al. Micro RNA 100 sensitizes luminal a breast cancer cells to paclitaxel treatment in part by targeting mTOR. Oncotarget. 2016;7:5702-5714. DOI: 10.18632/oncotarget.6790
  58. 58. Yang Q , Wang Y, Lu X, Zhao Z, Zhu L, Chen S, et al. MiR-125b regulates epithelial-mesenchymal transition via targeting Sema4C in paclitaxel-resistant breast cancer cells. Oncotarget. 2015;6:3268-3279. DOI: 10.18632/oncotarget.3065
  59. 59. Zhou M, Liu Z, Zhao Y, Ding Y, Liu H, Xi Y, et al. MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression. The Journal of Biological Chemistry. 2010;285:21496-21507. DOI: 10.1074/jbc.M109.083337
  60. 60. Bockhorn J, Dalton R, Nwachukwu C, Huang S, Prat A, Yee K, et al. MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nature Communications. 2013;4:1393. DOI: 10.1038/ncomms2393
  61. 61. Wu M-Y, Fu J, Xiao X, Wu J, Wu R-C. MiR-34a regulates therapy resistance by targeting HDAC1 and HDAC7 in breast cancer. Cancer Letters. 2014;354:311-319. DOI: 10.1016/j.canlet.2014.08.031
  62. 62. Hu W, Tan C, He Y, Zhang G, Xu Y, Tang J. Functional miRNAs in breast cancer drug resistance. OncoTargets and Therapy. 2018;11:1529-1541. DOI: 10.2147/OTT.S152462
  63. 63. EBCTCG, Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771. DOI: 10.1016/S0140-6736(11)60993-8
  64. 64. Cui J, Yang Y, Li H, Leng Y, Qian K, Huang Q , et al. MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells. Oncogene. 2015;34:3895-3907. DOI: 10.1038/onc.2014.430
  65. 65. Cittelly DM, Das PM, Salvo VA, Fonseca JP, Burow ME, Jones FE. Oncogenic HER2{Delta}16 suppresses miR-15a/16 and deregulates BCL-2 to promote endocrine resistance of breast tumors. Carcinogenesis. 2010;31:2049-2057. DOI: 10.1093/carcin/bgq192
  66. 66. Lü M, Ding K, Zhang G, Yin M, Yao G, Tian H, et al. MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRγ. Scientific Reports. 2015;5:8735. DOI: 10.1038/srep08735
  67. 67. Liu Z-R, Song Y, Wan L-H, Zhang Y-Y, Zhou L-M. Over-expression of miR-451a can enhance the sensitivity of breast cancer cells to tamoxifen by regulating 14-3-3ζ, estrogen receptor α, and autophagy. Life Sciences. 2016;149:104-113. DOI: 10.1016/j.lfs.2016.02.059
  68. 68. Yu X, Luo A, Liu Y, Wang S, Li Y, Shi W, et al. MiR-214 increases the sensitivity of breast cancer cells to tamoxifen and fulvestrant through inhibition of autophagy. Molecular Cancer. 2015;14:208. DOI: 10.1186/s12943-015-0480-4
  69. 69. Ward A, Balwierz A, Zhang JD, Küblbeck M, Pawitan Y, Hielscher T, et al. Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene. 2013;32:1173-1182. DOI: 10.1038/onc.2012.128
  70. 70. Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato W, Shigekawa T, et al. miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A. Scientific Reports. 2015;5:13170. DOI: 10.1038/srep13170
  71. 71. Ujihira T, Ikeda K, Suzuki T, Yamaga R, Sato W, Horie-Inoue K, et al. MicroRNA-574-3p, identified by microRNA library-based functional screening, modulates tamoxifen response in breast cancer. Scientific Reports. 2015;5:7641. DOI: 10.1038/srep07641
  72. 72. Sachdeva M, Wu H, Ru P, Hwang L, Trieu V, Mo Y-Y. MicroRNA-101-mediated Akt activation and estrogen-independent growth. Oncogene. 2011;30:822-831. DOI: 10.1038/onc.2010.463
  73. 73. Zugmaier G, Ennis BW, Deschauer B, Katz D, Knabbe C, Wilding G, et al. Transforming growth factors type β1 and β2 are equipotent growth inhibitors of human breast cancer cell lines. Journal of Cellular Physiology. 1989;141:353-361. DOI: 10.1002/jcp.1041410217
  74. 74. McEarchern JA, Kobie JJ, Mack V, Wu RS, Meade-Tollin L, Arteaga CL, et al. Invasion and metastasis of a mammary tumor involves TGF-beta signaling. International Journal of Cancer. 2001;91:76-82
  75. 75. Shi W, Gerster K, Alajez NM, Tsang J, Waldron L, Pintilie M, et al. MicroRNA-301 mediates proliferation and invasion in human breast Cancer. Cancer Research. 2011;71:2926-2937. DOI: 10.1158/0008-5472.CAN-10-3369
  76. 76. Zhao Y, Liu H, Liu Z, Ding Y, Ledoux SP, Wilson GL, et al. Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism. Cancer Research. 2011;71:4585-4597. DOI: 10.1158/0008-5472.CAN-11-0127
  77. 77. Gong C, Yao Y, Wang Y, Liu B, Wu W, Chen J, et al. Up-regulation ofmiR-21mediates resistance to Trastuzumab therapy for breast cancer. The Journal of Biological Chemistry. 2011;286:19127-19137. DOI: 10.1074/jbc.M110.216887
  78. 78. Dall P, Lenzen G, Gohler T, Lerchenmuller C, Feisel-Schwickardi G, Koch T, et al. Trastuzumab in the treatment of elderly patients with early breast cancer: Results from an observational study in Germany. Journal of Geriatric Oncology. 2015;6:462-469. DOI: 10.1016/j.jgo.2015.06.003
  79. 79. De Mattos-Arruda L, Bottai G, Nuciforo PG, Di Tommaso L, Giovannetti E, Peg V, et al. MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients. Oncotarget. 2015;6:37269-37280. DOI: 10.18632/oncotarget.5495
  80. 80. Ye X-M, Zhu H-Y, Bai W-D, Wang T, Wang L, Chen Y, et al. Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R. BMC Cancer. 2014;14:134. DOI: 10.1186/1471-2407-14-134
  81. 81. Russo F, Di Bella S, Nigita G, Macca V, Lagana A, Giugno R, et al. miRandola: extracellular circulating microRNAs database. PLoS One. 2012;7:e47786. DOI: 10.1371/journal.pone.0047786
  82. 82. Falcone G, Felsani A, D’Agnano I. Signaling by exosomal microRNAs in cancer. Journal of Experimental and Clinical Cancer Research. 2015;34:32. DOI: 10.1186/s13046-015-0148-3
  83. 83. Yu D, Wu Y, Zhang X, Lv M, Chen W, Chen X, et al. Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222. Tumor Biology. 2016;37:3227-3235. DOI: 10.1007/s13277-015-4161-0
  84. 84. Yang M, Chen J, Su F, Yu B, Su F, Lin L, et al. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Molecular Cancer. 2011;10:117. DOI: 10.1186/1476-4598-10-117
  85. 85. Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, et al. Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLoS One. 2014;9:e88193. DOI: 10.1371/journal.pone.0088193
  86. 86. Hannafon BN, Ding WQ. Intercellular communication by exosome-derived microRNAs in cancer. International Journal of Molecular Sciences. 2013;14:14240-14269. DOI: 10.3390/ijms140714240
  87. 87. Bader AG, Brown D, Winkler M. The promise of microRNA replacement therapy. Cancer Research. 2010;70:7027-7030. DOI: 10.1158/0008-5472.CAN-10-2010
  88. 88. Esau CC. Inhibition of microRNA with antisense oligonucleotides. Methods. 2008;44:55-60. DOI: 10.1016/j.ymeth.2007.11.001
  89. 89. Elmén J, Lindow M, Schütz S, Lawrence M, Petri A, Obad S, et al. LNA-mediated microRNA silencing in non-human primates. Nature. 2008;452:896-899. DOI: 10.1038/nature06783
  90. 90. Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685-689. DOI: 10.1038/nature04303
  91. 91. Majid S, Dahiya R. MicroRNA based therapeutic strategies for cancer: Emphasis on advances in renal cell carcinoma. In: MicroRNA Targeted Cancer Therapy. Cham: Springer International Publishing; 2014. pp. 175-188
  92. 92. Romero-Cordoba S, Rodriguez-Cuevas S, Rebollar-Vega R, Quintanar-Jurado V, Maffuz-Aziz A, Jimenez-Sanchez G, et al. Identification and pathway analysis of microRNAs with No previous involvement in breast cancer. PLoS One. 2012;7:e31904. DOI: 10.1371/journal.pone.0031904
  93. 93. Zheng S-R, Guo G-L, Zhai Q , Zou Z-Y, Zhang W. Effects of miR-155 antisense oligonucleotide on breast carcinoma cell line MDA-MB-157 and implanted tumors. Asian Pacific Journal of Cancer Prevention. 2013;14:2361-2366
  94. 94. Jiang L, Yu L, Zhang X, Lei F, Wang L, Liu X, et al. miR-892b silencing activates NF-B and promotes aggressiveness in breast Cancer. Cancer Research. 2016;76:1101-1111. DOI: 10.1158/0008-5472.CAN-15-1770
  95. 95. Tseng C-W, Huang H-C, Shih AC-C, Chang Y-Y, Hsu C-C, Chang J-Y, et al. Revealing the anti-tumor effect of artificial miRNA p-27-5p on human breast carcinoma cell line T-47D. International Journal of Molecular Sciences. 2012;13:6352-6369. DOI: 10.3390/ijms13056352
  96. 96. Liang Z, Wu H, Reddy S, Zhu A, Wang S, Blevins D, et al. Blockade of invasion and metastasis of breast cancer cells via targeting CXCR4 with an artificial microRNA. Biochemical and Biophysical Research Communications. 2007;363:542-546. DOI: 10.1016/j.bbrc.2007.09.007
  97. 97. Chakraborty C, Sharma AR, Sharma G, George C, Doss P, Lee S-S. Therapeutic miRNA and siRNA: Moving from bench to clinic as next generation medicine. 15 Sep 2017;8:132-143. DOI: 10.1016/j.omtn.2017.06.005
  98. 98. Beg MS, Brenner AJ, Sachdev J, Borad M, Kang Y-K, Stoudemire J, et al. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investigational New Drugs. 2017;35:180-188. DOI: 10.1007/s10637-016-0407-y
  99. 99. Kodahl AR, Lyng MB, Binder H, Cold S, Gravgaard K, Knoop AS, et al. Novel circulating microRNA signature as a potential non-invasive multi-marker test in ER-positive early-stage breast cancer: A case control study. Molecular Oncology. 2014;8:874-883. DOI: 10.1016/j.molonc.2014.03.002
  100. 100. Shimomura A, Shiino S, Kawauchi J, Takizawa S, Sakamoto H, Matsuzaki J, et al. Novel combination of serum microRNA for detecting breast cancer in the early stage. Cancer Science. 2016;107:326-334. DOI: 10.1111/cas.12880
  101. 101. Sochor M, Basova P, Pesta M, Dusilkova N, Bartos J, Burda P, et al. Oncogenic MicroRNAs: miR-155, miR-19a, miR-181b, and miR-24 enable monitoring of early breast cancer in serum. BMC Cancer. 2014;14:448. DOI: 10.1186/1471-2407-14-448
  102. 102. Chan M, Liaw CS, Ji SM, Tan HH, Wong CY, Thike AA, et al. Identification of circulating MicroRNA signatures for breast cancer detection. Clinical Cancer Research. 2013;19:4477-4487. DOI: 10.1158/1078-0432.CCR-12-3401
  103. 103. Li X-X, Gao S-Y, Wang P-Y,Zhou X, Li Y-J, Yu Y, et al. Reduced expression levels of let-7c in human breast cancer patients. Oncology Letters. 2015;9:1207-1212. DOI: 10.3892/ol.2015.2877
  104. 104. Qattan A, Intabli H, Alkhayal W, Eltabache C, Tweigieri T, Amer SB. Robust expression of tumor suppressor miRNA’s let-7 and miR-195 detected in plasma of Saudi female breast cancer patients. BMC Cancer. 2017;17:799. DOI: 10.1186/s12885-017-3776-5
  105. 105. Kleivi Sahlberg K, Bottai G, Naume B, Burwinkel B, Calin GA, Borresen-Dale A-L, et al. A serum microRNA signature predicts tumor relapse and survival in triple-negative breast cancer patients. Clinical Cancer Research. 2015;21:1207-1214. DOI: 10.1158/1078-0432.CCR-14-2011
  106. 106. Luo Y, Wang X, Niu W, Wang H, Wen Q , Fan S, et al. Elevated microRNA-125b levels predict a worse prognosis in HER2-positive breast cancer patients. Oncology Letters. 2017;13:867-874. DOI: 10.3892/ol.2016.5482
  107. 107. Sun Y, Wang M, Lin G, Sun S, Li X, Qi J, et al. Serum MicroRNA-155 as a potential biomarker to track disease in breast cancer. PLoS One. 2012;7:e47003. DOI: 10.1371/journal.pone.0047003
  108. 108. Heneghan HM, Miller N, Kelly R, Newell J, Kerin MJ. Systemic miRNA-195 differentiates breast cancer from other malignancies and is a potential biomarker for detecting noninvasive and early stage disease. The Oncologist. 2010;15:673-682. DOI: 10.1634/theoncologist.2010-0103
  109. 109. Schwarzenbach H, Milde-Langosch K, Steinbach B, Müller V, Pantel K. Diagnostic potential of PTEN-targeting miR-214 in the blood of breast cancer patients. Breast Cancer Research and Treatment. 2012;134:933-941. DOI: 10.1007/s10549-012-1988-6
  110. 110. Cuk K, Zucknick M, Madhavan D, Schott S, Golatta M, Heil J, et al. Plasma MicroRNA panel for minimally invasive detection of breast Cancer. PLoS One. 2013;8:e76729. DOI: 10.1371/journal.pone.0076729
  111. 111. Shen J, Hu Q , Schrauder M, Yan L, Wang D, Liu S. Circulating miR-148b and miR-133a as biomarkers for breast cancer detection. Oncotarget. 2014;5:5284-5294. Available from:
  112. 112. Zearo S, Kim E, Zhu Y, Zhao JT, Sidhu SB, Robinson BG, et al. MicroRNA-484 is more highly expressed in serum of early breast cancer patients compared to healthy volunteers. BMC Cancer. 2014;14:200. DOI: 10.1186/1471-2407-14-200
  113. 113. Matamala N, Vargas MT, Gonzalez-Campora R, Minambres R, Arias JI, Menendez P, et al. Tumor microRNA expression profiling identifies circulating microRNAs for early breast cancer detection. Clinical Chemistry. 2015;61:1098-1106. DOI: 10.1373/clinchem.2015.238691
  114. 114. Wang P-Y, Gong H-T, Li B-F, Lv C-L, Wang H-T, Zhou H-H, et al. Higher expression of circulating miR-182 as a novel biomarker for breast cancer. Oncology Letters. 2013;6:1681-1686. DOI: 10.3892/ol.2013.1593
  115. 115. Waters PS, Dwyer RM, Brougham C, Glynn CL, Wall D, Hyland P, et al. Impact of tumour epithelial subtype on circulating microRNAs in breast cancer patients. PLoS One. 2014;9:e90605. DOI: 10.1371/journal.pone.0090605
  116. 116. Zhu W, Qin W, Atasoy U, Sauter ER. Circulating microRNAs in breast cancer and healthy subjects. BMC Research Notes. 2009;2:89. DOI: 10.1186/1756-0500-2-89
  117. 117. Wang F, Zheng Z, Guo J, Ding X. Correlation and quantitation of microRNA aberrant expression in tissues and sera from patients with breast tumor. Gynecologic Oncology. 2010;119:586-593. DOI: 10.1016/j.ygyno.2010.07.021
  118. 118. Hamam R, Ali AM, Alsaleh KA, Kassem M, Alfayez M, Aldahmash A, et al. microRNA expression profiling on individual breast cancer patients identifies novel panel of circulating microRNA for early detection. Scientific Reports. 2016;6:25997. DOI: 10.1038/srep25997
  119. 119. Joosse SA, Müller V, Steinbach B, Pantel K, Schwarzenbach H. Circulating cell-free cancer-testis MAGE-A RNA, BORIS RNA, let-7b and miR-202 in the blood of patients with breast cancer and benign breast diseases. British Journal of Cancer. 2014;111:909-917. DOI: 10.1038/bjc.2014.360
  120. 120. Mangolini A, Ferracin M, Zanzi MV, Saccenti E, Ebnaof SO, Poma VV, et al. Diagnostic and prognostic microRNAs in the serum of breast cancer patients measured by droplet digital PCR. Biomarker Research. 2015;3:12. DOI: 10.1186/s40364-015-0037-0
  121. 121. Chen W, Cai F, Zhang B, Barekati Z, Zhong XY. The level of circulating miRNA-10b and miRNA-373 in detecting lymph node metastasis of breast cancer: Potential biomarkers. Tumor Biology. 2013;34:455-462. DOI: 10.1007/s13277-012-0570-5
  122. 122. Roth C, Rack B, Muller V, Janni W, Pantel K, Schwarzenbach H. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Research. 2010;12:R90. DOI: 10.1186/bcr2766
  123. 123. Shaker O, Maher M, Nassar Y, Morcos G, Gad Z. Role of microRNAs -29b-2, -155, -197 and -205 as diagnostic biomarkers in serum of breast cancer females. Gene. 2015;560:77-82. DOI: 10.1016/J.GENE.2015.01.062
  124. 124. Si H, Sun X, Chen Y, Cao Y, Chen S, Wang H, et al. Circulating microRNA-92a and microRNA-21 as novel minimally invasive biomarkers for primary breast cancer. Journal of Cancer Research and Clinical Oncology. 2013;139:223-229. DOI: 10.1007/s00432-012-1315-y
  125. 125. Huo D, Clayton W, Yoshimatsu T, Chen J, Olopade O. Identification of a circulating microRNA signature to distinguish recurrence in breast cancer patients. Oncotarget. 2016;7:55231-55248.
  126. 126. Eichelser C, Flesch-Janys D, Chang-Claude J, Pantel K, Schwarzenbach H. Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR-34a, miR-155, and miR-373 in human breast cancer development and progression. Clinical Chemistry. 2013;59:1489-1496. DOI: 10.1373/clinchem.2013.205161
  127. 127. Wang H, Tan G, Dong L, Cheng L, Li K, Wang Z, et al. Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS One. 2012;7:e34210. DOI: 10.1371/journal.pone.0034210
  128. 128. Wu X, Somlo G, Yu Y, Palomares MR, Li A, Zhou W, et al. De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer. Journal of Translational Medicine. 2012;10:42. DOI: 10.1186/1479-5876-10-42

Written By

Amal Qattan

Submitted: March 26th, 2019 Reviewed: July 8th, 2019 Published: August 17th, 2019