After an initial screening based on these predefined criteria, a total of 18624 records were identified. Through a meticulous evaluation process, 186 papers that precisely met the research objectives were included in this review. Conversely, 18438 studies were excluded due to their clear irrelevance to the core research questions and aims as defined by the inclusion and exclusion criteria.

miRNAs have emerged as critical regulators in the complex network of gene expression, significantly influencing tumorigenesis and cancer progression. Aberrant expression of miRNAs can lead to the dysregulation of oncogenes and tumor suppressor genes, thereby contributing to various stages of cancer development, including initiation, proliferation, invasion, metastasis, and resistance to therapy (11, 39).

miRNAs play a pivotal role in the regulation of gene expression and have been implicated in the pathogenesis of various cancers, including breast cancer. Alterations in miRNA expression profiles have been observed in breast cancer tissues and cell lines, suggesting their involvement in tumor initiation, progression, and metastasis (48).

Several studies have performed comprehensive miRNA expression profiling to identify miRNAs that are differentially expressed in breast cancer compared to normal breast tissue. Iorio et al. conducted one of the earliest studies, identifying a set of miRNAs consistently deregulated in breast cancer samples (12). They reported overexpression of oncomiRs such as miR-21, miR-155, and downregulation of tumor suppressor miRNAs like miR-125b and miR-145. miR-21 promotes the growth, invasion and metastasis of tumor cells by affecting TGFB, a multifunctional cytokine. miR-125b downregulation may contribute to tumor initiation and progression by affecting target genes such as YES, ETS1, TEL, AKT3 which can lead to impaired differentiation capacity of cancer cells. Blenkiron et al. identified miRNA signatures associated with estrogen receptor (ER), progesterone receptor (PR), and HER2 status (49). For instance, miR-210 was found to be upregulated in HER2-positive tumors. Interestingly, Wu et al. demonstrated that plasma levels of miR-205 and miR-155 were significantly elevated in breast cancer patients compared to healthy controls (50). Correspondingly, treatment modalities can also influence miRNA expression in breast cancer cells. Adams et al. observed that miR-206 expression was upregulated in breast cancer cells treated with anti-estrogen therapies, suggesting a role in endocrine resistance (51).

Epigenetic mechanisms, such as DNA methylation and histone modifications, can regulate miRNA expression in breast cancer. Mulrane et al. performed integrated miRNA and mRNA expression profiling to identify epigenetically deregulated miRNAs in breast cancer cell lines (52). They found that hypermethylation of miRNA gene promoters led to decreased expression of tumor-suppressive miRNAs, contributing to tumor progression. Similarly, Liu et al. found that M6A modification is involved in miRNA biogenesis, and aberrant M6A modification may aggravate tumor progression (53).Pan et al. revealed that methyltransferase-like 3 (METTL3) accelerates the maturation of miR-221-3p and enhances the expression of miR-221-3p by increasing the M6A modification of pri-miR-221-3p, while promote the resistance of breast cancer cells to adriamycin(ADR) through the METTL3/miR-221–3 p/Hipk2/Che -1 axis. Conversely, inhibition of miR-221-3p decreased tumor growth and reversed METTL3 overexpression-induced drug resistance (54).

miRNAs play a pivotal role in regulating gene expression and have been critically implicated in breast cancer progression by modulating cell proliferation and apoptosis (55, 56). By targeting specific mRNAs, miRNAs can function as oncogenes or tumor suppressors, thereby influencing tumor growth and development ( Figure 2 ).

For instance, miR-124 has been identified to target the transcription factor activating enhancer-binding protein 4 (TFAP4), leading to the inhibition of growth and invasion of breast cancer cells (57). Overexpression of miR-124 significantly reduces cell proliferation and promotes apoptosis, suggesting its potential as a therapeutic target (57). Similarly, miR-218 suppress cancer progression by targeting the 3’-UTR regions of CDK6 and cyclin D1, as demonstrated in gastric cancer studies, indicating a possible analogous mechanism in breast cancer (58).

miR-34a functions as a tumor suppressor by regulating genes involved in apoptosis, such as Notch1, leading to increased apoptosis in breast cancer cells (59). On the contrary, miR-155 is overexpressed in breast cancer and acts as an oncogenic miRNA by promoting cell proliferation and inhibiting apoptosis (12).

miR-21, another oncogenic miRNA, is commonly overexpressed in breast cancer and facilitates tumor cell proliferation while inhibiting apoptosis by targeting tumor suppressor genes like PDCD4 (60). The miR-200 family also plays a significant role in regulating EMT, thus affecting proliferation and apoptosis in breast cancer cells (61).

Moreover, miR-7 inhibits epithelial-to-mesenchymal transition (EMT) and metastasis of breast cancer cells by targeting focal adhesion kinase (FAK) expression (62). The upregulation of miR-7 suppresses proliferation and induces apoptosis in breast cancer cells (62). Additionally, miR-10a has been shown to regulate migration and invasion in glioma through EMT modulation via EphA8, suggesting its potential involvement in breast cancer metastasis (63).

Furthermore, miR-221 and miR-222 promote proliferation by targeting cell cycle regulators such as p27^Kip1 and estrogen receptor alpha (ERα), with their upregulation correlating with increased invasiveness and poor prognosis in breast cancer patients (64). Conversely, miR-15a and miR-16–1 induce apoptosis and inhibit tumor growth by targeting the anti-apoptotic gene BCL-2 (28).

miRNAs play critical roles in the regulation of gene expression involved in cancer progression, particularly in the invasion and metastasis of breast cancer cells (65, 66). These small non-coding RNAs can function as oncogenes or tumor suppressors by targeting mRNAs that encode proteins essential for cell adhesion, migration, and invasion ( Figure 3 ).

One of the most studied miRNAs in breast cancer metastasis is miR-10b. Liu et al. demonstrated that miR-10b targets E-cadherin, a key cell-cell adhesion molecule, thereby promoting breast cancer metastasis (65). The downregulation of E-cadherin leads to decreased cell adhesion and increased cell motility, facilitating metastatic spread (65). Similarly, Ma et al. found that therapeutic silencing of miR-10b in a mouse mammary tumor model significantly inhibited metastasis without affecting primary tumor growth, highlighting miR-10b as a potential therapeutic target (47, 66).

miR-125b has been implicated in breast cancer invasion and chemoresistance. Wang et al. reported that circulating miR-125b serves as a marker for predicting chemoresistance in breast cancer patients (67). Elevated levels of miR-125b are associated with enhanced invasion and poor response to chemotherapy, suggesting its role in metastasis and treatment outcomes (67).

Another tumor-suppressive miRNA, miR-143, is often downregulated in breast cancer tissues. Du et al. showed that miR-143 suppresses tumor proliferation and bone metastasis by targeting MAPK3 (68). Restoration of miR-143 levels led to inhibited cell migration and invasion, underscoring its potential as a therapeutic agent (68).

miR-373 and miR-520c have been identified as promoters of tumor invasion and metastasis. Huang et al. demonstrated that these miRNAs enhance metastatic capabilities by downregulating tumor suppressor genes and activating pro-metastatic genes. Specifically, they target genes involved in cell adhesion and cytoskeletal rearrangement, facilitating tumor cell dissemination (69, 70).

Additionally, miR-21 is overexpressed in breast cancer and contributes to invasion and metastasis by targeting tumor suppressor genes such as PTEN and RECK (71, 72). This overexpression correlates with poor prognosis and increased metastatic potential (71). miR-155 also promotes metastasis by targeting SOCS1, leading to the activation of the JAK2/STAT3 signaling pathway, which enhances cell migration and invasion (45, 73).

Conversely, the miR-200 family functions as metastasis suppressors by inhibiting epithelial-to-mesenchymal transition (EMT), a process crucial for cancer metastasis (61, 74). They target transcriptional repressors ZEB1 and ZEB2, which are key regulators of EMT (74). Loss of miR-200 expression is associated with increased invasiveness and metastatic potential (61).

miR-34a acts as a tumor suppressor by targeting genes involved in EMT and metastasis, such as Notch1 and Fra-1, thereby reducing cell invasion and metastasis (75, 76).

Moreover, miR-9 promotes metastasis by directly targeting E-cadherin and activating β-catenin signaling, which enhances cell motility and invasiveness (77). High miR-9 expression levels correlate with advanced tumor stages and poor patient prognosis (77).

Early detection of breast cancer significantly improves patient prognosis and survival rate (78). Traditional diagnostic methods, such as mammography and tissue biopsy, have limitations including invasiveness, cost, and sometimes insufficient sensitivity and specificity (79). Therefore, there is a pressing need for non-invasive, reliable biomarkers for early breast cancer detection. miRNAs, small non-coding RNAs involved in post-transcriptional gene regulation, have emerged as promising diagnostic biomarkers due to their stability in bodily fluids and their altered expression profiles in cancer patients (14, 80).

Circulating miRNAs in serum and plasma have been extensively studied as potential diagnostic tools for breast cancer. Shimomura et al. identified a novel combination of serum miRNAs, including miR-1246 and miR-1307-3p, which could effectively detect breast cancer at early stages (81). Their study demonstrated that these miRNAs had high sensitivity and specificity, suggesting their utility in clinical diagnostics (81).

Similarly, Wu et al. employed next-generation sequencing to profile miRNAs in breast cancer patients, identifying several miRNAs with differential expression that could serve as potential biomarkers (50). Among these, miR-21 and miR-221 were significantly upregulated in breast cancer patients compared to healthy controls (50), consistent with previous reports linking these miRNAs to breast cancer development (12, 82).

Eichelser et al. reported deregulated serum concentrations of circulating cell-free miR-17, miR-34a, miR-155, and miR-373 in breast cancer patients (83). Their findings indicated that these miRNAs could reflect tumor dynamics and might be used to monitor disease progression (83). Moreover, miR-155 has been widely studied and is considered a key player in breast cancer pathogenesis (84, 85).

Kodahl et al. identified a novel circulating miRNA signature as a potential non-invasive multi-marker test in estrogen receptor-positive early-stage breast cancer (86). Their case-control study suggested that a combination of miRNAs could improve diagnostic accuracy (86).

In addition to these studies, other miRNAs have been identified as potential diagnostic biomarkers. Heneghan et al. demonstrated that miR-195 was significantly elevated in the blood of breast cancer patients, distinguishing them from healthy individuals (87). Similarly, Chan et al. identified a panel of circulating miRNAs, including miR-145 and miR-451, that could serve as biomarkers for breast cancer detection (88).

The stability of miRNAs in circulating blood is attributed to their encapsulation within exosomes or association with RNA-binding proteins, protecting them from RNase degradation (89). This property enhances their potential as reliable biomarkers (89, 90).

Despite promising results, there are challenges in translating miRNA biomarkers into clinical practice. Variability in miRNA expression due to sample processing, patient heterogeneity, and detection methods can affect reproducibility (91). Thus, the Standardized of protocols and larger-scale validation studies are needed to confirm the clinical utility of miRNAs as diagnostic biomarkers (92).

Circulating miRNAs in blood have emerged as promising non-invasive biomarkers for the early detection, prognosis, and monitoring of breast cancer (93, 94). Due to their stability in body fluids and their specific expression profiles associated with various pathological conditions, detecting circulating miRNAs has gained significant attention in cancer research (90, 95).

Several analytical techniques have been developed and optimized for the detection and quantification of circulating miRNAs in blood samples. The most commonly used methods include quantitative real-time PCR (qRT-PCR), microarray analysis, and next-generation sequencing (NGS).

qRT-PCR is widely used due to its high sensitivity, specificity, and quantitative capabilities (91). It involves reverse transcription of miRNAs into cDNA followed by amplification using specific primers. This method requires careful normalization using stable endogenous controls or spiked-in synthetic miRNAs to account for variations in sample processing and RNA extraction efficiency (96, 97).

Microarray platforms enable the simultaneous detection of hundreds of miRNAs, providing a comprehensive expression profile (98). However, microarrays have limitations in sensitivity and dynamic range compared to qRT-PCR and NGS. They are useful for initial screening studies to identify differentially expressed miRNAs in patient samples (87).

Next-Generation Sequencing (NGS) allows for high-throughput sequencing of small RNAs, offering the most comprehensive analysis of the miRNA transcriptome, including the discovery of novel miRNAs (99, 100). Wu et al. utilized NGS to profile miRNAs in breast cancer patients, identifying specific miRNAs with potential diagnostic value (50).

Despite technological advances, detecting circulating miRNAs presents several challenges. The low abundance of miRNAs in circulation requires highly sensitive detection methods (101). Additionally, the presence of hemolysis can release intracellular miRNAs from blood cells, confounding results (102). Standardization of sample collection, processing, and data normalization is crucial for obtaining reliable and reproducible results (92, 103).

In breast cancer, numerous studies have focused on detecting circulating miRNAs as diagnostic and prognostic biomarkers. For example, Shimomura et al. identified a panel of serum miRNAs that could effectively detect early-stage breast cancer using qRT-PCR. Other studies have demonstrated the feasibility of using circulating miRNAs to monitor treatment response and disease progression (104, 105).

Silva et al. examined vesicle-related miRNAs in plasma and their correlation with survival in lung cancer patients, highlighting the potential of exosome-associated miRNAs as biomarkers (106). Similar approaches have been applied in breast cancer to isolate exosomal miRNAs, which may offer increased specificity and stability (107, 108).

The detection of circulating miRNAs in blood represents a promising avenue for the development of non-invasive diagnostic tools in breast cancer. Advances in detection technologies and standardization of methodologies will enhance the reliability of circulating miRNAs as biomarkers, potentially improving early detection and patient outcomes.

miRNAs have emerged as critical regulators in cancer biology, including breast cancer, by modulating gene expression at the post-transcriptional level (109, 110). The dysregulation of specific miRNAs in breast cancer has provided a rationale for developing miRNA-targeted therapeutic strategies aimed at restoring normal miRNA function or inhibiting oncomiRs (111, 112).

miRNA replacement therapy involves restoring the expression of tumor-suppressive miRNAs that are downregulated in cancer cells (113). Synthetic miRNA mimics are designed to replicate the function of endogenous miRNAs. Bader et al. highlighted the potential of miRNA replacement therapy, emphasizing its ability to target multiple oncogenic pathways simultaneously (109). For instance, the restoration of miR-34a, a well-known tumor suppressor, has shown significant anti-tumor effects in preclinical models of breast cancer (114, 115).

The first miRNA mimic to enter clinical trials was MRX34, a liposomal miR-34a mimic, demonstrating the translational potential of this strategy (116). Although the phase I clinical trial was halted due to immune-related adverse events, it provided valuable insights into the challenges and considerations in miRNA therapeutics (116, 117).

oncomiRs can be inhibited using antisense oligonucleotides (anti-miRs), locked nucleic acids (LNAs), or miRNA sponges (118, 119). These molecules are designed to specifically bind to and inhibit the function of target miRNAs. Adams et al. discussed the aberrant regulation and function of miRNAs in cancer and the therapeutic potential of miRNA inhibition (112).For example, inhibition of miR-21, an oncomiR overexpressed in breast cancer, using antisense oligonucleotides resulted in decreased tumor growth and increased apoptosis in preclinical studies (120). Similarly, targeting miR-155 has shown promise in reducing breast cancer proliferation and metastasis (67).

Effective delivery of miRNA therapeutics remains a significant challenge due to issues related to stability, specificity, and off-target effects (121, 122). Various delivery systems have been explored, including lipid nanoparticles, viral vectors, and extracellular vesicles (123, 124).Van Zandwijk et al. conducted a phase I study using miRNA-loaded minicells for patients with recurrent malignant pleural mesothelioma, demonstrating the feasibility of systemic miRNA delivery (110). Although the study was in mesothelioma patients, the approach provides a framework that could be applied to breast cancer therapy.

Several clinical trials are underway to evaluate the safety and efficacy of miRNA-based therapeutics. Cortez et al. emphasized the role of miRNAs in body fluids as both hormones and biomarkers, underlining their potential in cancer therapy (111). The ongoing research focuses on optimizing delivery methods, improving specificity, and minimizing adverse effects (125, 126).

Despite the promising potential of miRNA-targeted therapies, challenges such as immune activation, off-target effects, and delivery efficiency need to be addressed (127). Bouchie highlighted the entry of the first miRNA mimic into clinical trials as a significant milestone, yet also pointed out the hurdles that remain (113).

Future strategies may involve the use of combinational therapies, personalized medicine approaches, and advanced delivery systems to enhance the efficacy of miRNA therapeutics in breast cancer (128, 129).

miRNAs have emerged as critical modulators of gene expression in cancer cells, influencing various cellular processes such as proliferation, apoptosis, and response to therapy (94, 130). In breast cancer, the interplay between miRNAs and conventional therapies like chemotherapy and radiotherapy has gained significant attention, as miRNAs can modulate therapeutic efficacy and resistance mechanisms (131, 132).

miR-451 has been implicated in the resistance of breast cancer cells to the chemotherapeutic drug doxorubicin. Kovalchuk et al. found that overexpression of miR-451 in MCF-7 breast cancer cells led to increased sensitivity to doxorubicin by targeting the multidrug resistance protein MDR1 (133). Conversely, downregulation of miR-451 contributed to chemoresistance, indicating its role in modulating drug response (133).

Wang et al. reported that miR-122 inhibits cell proliferation and tumorigenesis in breast cancer by targeting the insulin-like growth factor 1 receptor (IGF1R) (134). IGF1R is known to confer resistance to chemotherapy and radiotherapy (135). By targeting IGF1R and regulate PI3K/Akt/mTOR/p70S6K pathway,miR-122 plays an important role in inhibiting the tumorigenesis (134).

miR-21 is frequently overexpressed in breast cancer and is associated with poor prognosis and therapy resistance (136, 137). Wang et al. highlighted miR-21 as a novel therapeutic target, as its overexpression promoted breast cancer cell proliferation and metastasis in vivo by targeting Leucine zipper transcription factor-like 1 (LZTFL1) (138). miR-21 regulates several targets involved in apoptosis and DNA repair, such as PTEN and PDCD4, influencing the response to therapy (71, 139).

The tumor microenvironment plays a crucial role in therapy resistance (140). Mao et al. discussed how stromal cells and miRNAs within the tumor microenvironment affect breast cancer progression and response to treatment (141). miRNAs can modulate the communication between cancer cells and stromal cells, impacting the efficacy of chemotherapy and radiotherapy (142).

miRNAs can influence therapy response through various mechanisms:

Understanding the role of miRNAs in therapy response opens avenues for combination treatments. Therapeutic strategies could involve:

miRNAs significantly impact the efficacy of chemotherapy and radiotherapy in breast cancer by modulating key pathways involved in drug response and resistance. Targeting specific miRNAs offers a promising strategy to enhance therapeutic outcomes and overcome resistance.

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide (78). Recent studies have highlighted the crucial role of miRNAs in cancer progression and patient prognosis (12, 36). miRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and have been implicated in various cellular processes, including proliferation, apoptosis, and metastasis (55). This section explores the relationship between specific miRNAs and the survival rates of breast cancer patients.

miR-29a has been shown to promote migration and invasion in breast cancer cells by targeting ten-eleven translocation 1 (TET1), thereby activating epithelial-mesenchymal transition (EMT) (148). Pei et al. reported that elevated levels of miR-29a are associated with poor overall survival in breast cancer patients, suggesting its potential as a prognostic biomarker (148).

Overexpression of miR-25 has been linked to tumor progression and unfavorable prognosis in breast cancer (149). miR-25 may contribute to cancer progression by targeting tumor suppressor genes and promoting cell cycle progression (150). Chen et al. found that miR-25-3p promotes proliferation by targeting tumor suppressor BTG2 (149).

Circulating miRNAs in plasma have been investigated as early detection markers for breast cancer (151). Cuk et al. identified a panel of miRNAs, including miR-155 and miR-21, whose elevated levels were associated with decreased survival rates (151). These miRNAs may serve as non-invasive biomarkers for early diagnosis and prognosis assessment (93).

While Wu et al. studied miR-9 in osteosarcoma (152), miR-9 has also been implicated in breast cancer. Elevated miR-9 levels are associated with enhanced metastasis and poor survival rates (77). miR-9 promotes epithelial-mesenchymal transition by targeting E-cadherin, facilitating tumor progression (77).

miR-21 is one of the most studied oncomiRs in breast cancer. Its overexpression is correlated with advanced tumor stage, metastasis, and reduced overall survival (153). miR-21 promotes tumor growth by targeting tumor suppressor genes such as PTEN and PDCD4 (154, 155). High miR-21 levels have been proposed as a predictor of poor prognosis (156).Similarly, miR-155 is overexpressed in breast cancer and is associated with aggressive tumor characteristics and decreased survival rates (144). Its role in promoting proliferation and inhibiting apoptosis contributes to tumor progression (73).

In contrast, miR-34a acts as a tumor suppressor and its reduced expression is linked to poor prognosis (157). Restoration of miR-34a levels inhibits tumor growth and enhances sensitivity to chemotherapy (158).

The miR-200 family is known for suppressing metastasis by inhibiting epithelial-mesenchymal transition (61). Lower expression levels of miR-200c have been associated with higher metastatic potential and worse survival outcomes (159).

miR-210 is upregulated under hypoxic conditions within tumors and is linked to poor prognosis in breast cancer patients (160). Its expression promotes angiogenesis and adaptation to hypoxia, facilitating tumor survival and progression (161).

miR-31 has been identified as a tumor suppressor, and higher levels are associated with reduced metastasis and improved survival rates (162). It inhibits multiple steps of the metastatic process, including invasion and colonization (163).

Understanding the relationship between specific miRNAs and patient survival can aid in the development of prognostic biomarkers and personalized therapies (131). miRNA expression profiling may help identify high-risk patients who could benefit from more aggressive treatment strategies (14).

miRNAs play a significant role in breast cancer progression and patient survival. Specific miRNAs such as miR-29a, miR-25, miR-21, and miR-155 are associated with poor prognosis, while others like miR-34a and miR-31 correlate with better survival outcomes. Further research into miRNA-based diagnostics and therapeutics holds promise for improving breast cancer patient management and survival rates.

Breast cancer prognosis remains a significant challenge due to the heterogeneity of the disease and the variability in patient outcomes (52, 164). Traditional prognostic factors, such as tumor size, lymph node status, and hormone receptor expression, do not fully capture the complexity of tumor biology (165). miRNAs, small non-coding RNAs that regulate gene expression post-transcriptionally, have emerged as promising prognostic biomarkers in breast cancer (98, 166). Their dysregulated expression in cancer tissues and presence in bodily fluids enable non-invasive prediction of disease progression and patient outcomes (14, 167).

miRNA dysregulation plays a critical role in breast cancer development and progression (12, 52). Mulrane et al. highlighted that specific miRNAs are consistently altered in breast cancer tissues, affecting cell proliferation, apoptosis, and metastasis (52). For instance, overexpression of oncomiRs such as miR-21 and miR-155 has been associated with poor prognosis and decreased overall survival (144, 153). Conversely, downregulation of tumor-suppressive miRNAs like miR-34a and miR-200c correlates with increased tumor aggressiveness and unfavorable outcomes (168, 169).

Circulating miRNAs in serum and plasma have garnered attention as minimally invasive prognostic biomarkers (90, 170). These miRNAs are remarkably stable in circulation due to their encapsulation within exosomes or association with RNA-binding proteins (89, 171). Erbes et al. demonstrated the feasibility of detecting circulating miRNAs in breast cancer patients, suggesting their potential in monitoring disease progression and response to therapy (166).

Several clinical studies have identified specific miRNAs with prognostic significance:

Wang et al. compared the miRNA spectrum between serum and plasma, concluding that both sources are suitable for miRNA biomarker discovery (98). However, they noted that certain miRNAs may show differential stability or abundance, emphasizing the need for standardized sample processing protocols (98, 102).

While the potential of miRNAs as prognostic biomarkers is promising, several challenges need to be addressed:

Advancements in high-throughput technologies and bioinformatics analysis are facilitating the discovery of novel miRNA biomarkers (177, 178). Integrating miRNA profiling with other molecular data, such as gene expression and proteomics, may provide a more comprehensive prognostic model (179). Additionally, exploring the functional roles of prognostic miRNAs could uncover new therapeutic targets ( Table 1 ).