The primary threat to survival in patients with BC arises from the highly invasive and migratory characteristics of tumor cells. These malignant cells break through tissue barriers via multiple pathological pathways and molecular mechanisms, causing systemic dissemination and eventually forming lethal metastatic lesions in distant organs (40). Numerous studies have recently confirmed that differential expression of the miR-200 family between epithelial and mesenchymal cells positions it as a key molecular regulator of BC invasion and migration. Members of this family significantly influence BC cell invasion and migration through multi-pathway and multi-target regulatory networks (Table I), providing critical insights into the mechanisms underlying BC metastasis.

Under normal physiological conditions, epithelial cells maintain tissue integrity through tight junctions, adherens junctions and other cellular structures. These features provide strong adhesion and limit migratory capability. Mesenchymal cells, by contrast, show reduced cell-cell adhesion and reorganized cytoskeletal structures, resulting in increased motility and invasiveness. EMT refers to the transition from epithelial to mesenchymal phenotypes, characterized by the downregulation of epithelial markers (for example, E-cadherin) and the upregulation of mesenchymal markers (for example, N-cadherin and vimentin). This transformation allows tumor cells to gain migratory and invasive properties, significantly enhancing their metastatic potential (41). EMT is primarily mediated by core transcription factors, such as ZEB1, ZEB2, Snail and Twist, which repress epithelial gene expression by binding to E-box motifs in their promoter regions (42). Notably, a precise double-negative feedback loop exists between the miR-200 family and the ZEB family (ZEB1/ZEB2). On one hand, miR-200 family members directly target and suppress the expression of ZEB1 and ZEB2 (43-50), blocking EMT and inhibiting the invasive and migratory capacities of BC cells. Conversely, the ZEB family transcriptionally suppresses miR-200 family expression (51-53), thereby promoting EMT and increasing tumor metastatic potential. This reciprocal regulatory mechanism establishes a dynamic equilibrium that critically governs BC invasion and metastasis. Notably, this classical miR-200/ZEB feedback loop has also been identified as a central mechanism driving invasion and metastasis in various epithelial tumors, including OC (54) and colorectal cancer (CRC) (55), highlighting its conserved role in maintaining epithelial phenotypes and suppressing malignant transformation. In addition to the ZEB family, miR-200 family members further regulate tumor metastasis by targeting other drivers of EMT. For instance, the lncRNA ATB acts as a molecular sponge to competitively bind miR-200c, thereby alleviating its inhibitory effect on Twist. This interaction promotes EMT and enhances the invasive and migratory capabilities of BC cells (25). SIRT1 induces the epigenetic silencing of E-cadherin in BC (56). Eades et al (20) demonstrated that miR-200a targets and suppresses SIRT1 expression, thereby inhibiting EMT and reducing tumor invasion.

In addition, the miR-200 family regulates tumor EMT through several other mechanisms, thereby influencing tumor invasion and migration. Studies indicate that ELK3 acts synergistically with ZEB1 to suppress E-cadherin expression (57). Kim et al (21) demonstrated that miR-200a specifically binds to the 3'UTR of ELK3 mRNA, significantly reducing ELK3 protein levels, restoring E-cadherin expression, and suppressing BC cell invasion and migration. Kim et al (22) further showed that miR-200a targets and downregulates IMP2 and IMP3 expression, thereby blocking EMT and inhibiting cell migration and invasion. Another study revealed that the p38 MAPK subtype p38γ negatively regulates miR-200b expression by inhibiting its transcriptional activator GATA3. Conversely, miR-200b overexpression reduces Suz12 expression, reversing p38γ-induced EMT process (29). Additionally, miR-200b suppresses EMT by directly inhibiting Kindlin-2 (23). Peng et al (24) demonstrated that miR-200c blocks EMT and inhibits migration by directly targeting c-JUN. Tumor metastasis is a dynamic, reversible process. Tumor cells entering circulation must activate EMT to enhance invasive capacity; however, during implantation in distant organs, they must revert to epithelial characteristics via mesenchymal-epithelial transition (MET) to establish metastatic colonies (58). Zhou et al (26) found that in metastatic BC (MBC) lesions, the lncRNA H19 sequesters miR-200b/c, thereby relieving suppression of its target gene Git2. This results in Arf6 inactivation and maintains E-cadherin expression, thus inhibiting EMT and promoting MET, facilitating the colonization of metastatic sites (26). Collectively, these studies indicate that the miR-200 family influences EMT via a multi-level regulatory network, playing a pivotal role in BC metastasis.

Anoikis is a form of programmed cell death triggered when cells detach from the extracellular matrix or loss intercellular adhesion. It effectively limits the survival and migration of detached tumor cells. However, malignant tumor cells can acquire resistance to anoikis, promoting metastasis (59). The role of the miR-200 family in this process appears complex. It has been reported that the loss of YAP1 function can protect cells from anoikis (60). Yu et al (61) showed that miR-200a promotes metastasis by inhibiting YAP1, thereby inducing tumor cell resistance to anoikis. By contrast, Howe et al (62) reported that miR-200c restores apoptosis sensitivity by downregulating TrkB, thus suppressing cell migration. This functional discrepancy suggests that miR-200 family members may exhibit distinct roles depending on specific microenvironmental contexts. The underlying mechanisms require further exploration. Additionally, miR-200-mediated regulation of anoikis through the Orphanage pathway is not exclusive to BC. In endometrial carcinoma, miR-200 family members (miR-141 and miR-200b/200c/429) directly suppress Sestrin proteins (SESN2 and SESN3), weakening resistance to anoikis following loss of anchorage. This observation suggests that the miR-200/Sestrin axis may also play a critical role in endometrial carcinoma metastasis (63).

The miR-200 family also exerts its biological effects by regulating multiple genes involved in invasion and migration. Studies indicate that EPHA2 binds its ligand, Ephrin-A1, resulting in EPHA2 degradation and suppression of tumor invasion and migration. In the absence of Ephrin-A1, EPHA2 accumulates excessively, promoting invasion and migration (64). Tsouko et al (65) reported that Ephrin-A1 expression is nearly absent in triple-negative BC (TNBC), leading to elevated EPHA2 expression. miR-200a directly targets EPHA2, reducing its expression, thereby increasing AMPK activity and ultimately suppressing tumor cell invasion and migration (65). Additionally, miR-200a targets and downregulates connexin 43 (cx43) expression, thus inhibiting cellular metastasis (66). The ezrin-radixin-moesin (ERM) protein family is critical for maintaining cytoskeletal structure, facilitating cell movement, and contributing to BC invasion and migration (67). Studies have demonstrated that miR-200b downregulates ERM family proteins (Ezrin, Radixin and Moesin), disrupting cytoskeletal remodeling and inhibiting invasion (68-70). Additionally, Ren et al (27) showed that knockout of circDENND4C upregulates miR-200b/c, which suppresses glycolysis and MMP2/9 expression, consequently decreasing cell invasion. Other studies reported that miR-141-3p downregulates high-mobility group box 1 protein expression, suppressing hypoxia-induced HIF-1α pathway activity and cell migration (33). miR-429 can reduce BC bone metastasis by targeting and downregulating CRKL and MMP9 expression (71). However, a comprehensive study on the miR-200 family reported conflicting results. Stable overexpression of the miR-200b/200a/429 or miR-141/200c clusters inhibited MDA-MB-231 cell proliferation but significantly enhanced migration and invasion. Compared with miR-200b/200a/429, the miR-141/200c cluster showed stronger suppression of cell proliferation and greater promotion of migration and invasion. Further analysis revealed that overexpressing either miR-200b/200a/429 or miR-141/200c increased phosphorylation of FAK and AKT, thus enhancing cell migration and invasion. Compared with miR-200b/200a/429-overexpressing cells, those expressing miR-141/200c secreted higher levels of vascular endothelial growth factor A and exhibited increased integrin-αV expression, further augmenting migration and invasion (72). Additionally, Jin et al (73) suggested that the miR-200c/141 cluster promotes BC metastasis by upregulating SerpinB2 (PAI-2); however, the precise molecular mechanisms involved require further clarification. These discrepancies highlight the functional heterogeneity of the miR-200 family across different BC subtypes and TME.

Besides the aforementioned pathways, the miR-200 family can inhibit cell invasion and migration by targeting molecules such as protein kinase Cα (74), ARHGAP18 (75), PKA subunits (PRKAR1A and PRKACB) (76), ANP32E (77) and FUT4 (78). Furthermore, lncRNA NEAT1 acts as a sponge for miR-141-3p. Upon interference with NEAT1 expression, miR-141-3p levels significantly increase, thereby reducing KLF12 expression, inhibiting cell invasion and migration, and decreasing chemotherapy resistance (28). Conversely, FOXP3, as an endogenous tumor suppressor, inhibits BC metastasis by promoting the expression of miR-200c and miR-141 (30). Liu et al (79) notably reported that BC cells specifically package miR-200c into exosomes through a Rab1A-mediated sorting mechanism. The cells then actively secrete these exosomes, thereby evading the tumor suppressive effects of miR-200c, promoting metastasis, and reshaping the immune microenvironment. This finding reveals a novel mechanism underlying BC metastasis and suggests new therapeutic opportunities (79).

In summary, the miR-200 family plays a complex and critical role in BC invasion and metastasis through multiple pathways, including the regulation of EMT, anoikis, and invasion- and migration-related genes. Although most studies support its tumor-suppressive role, some findings suggest pro-metastatic effects. These discrepancies indicate that future research should clarify its regulatory mechanisms across BC subtypes and microenvironments. More broadly, pathways regulated by the miR-200 family, such as EMT and anoikis, represent core biological processes that enable cells to acquire migratory capabilities. Therefore, deepening the understanding of miR-200 family-regulated networks in cancer not only provides potential therapeutic targets for advanced metastatic disease but also suggests that monitoring these pathway activities in precancerous lesions or early-stage cancers may enable earlier intervention by predicting invasive potential.

The miR-200 family also plays an essential role in regulating BC cell proliferation and apoptosis. Its members influence tumor biological behaviors by targeting diverse signaling molecules (Table I). Current studies suggest that miR-200a, miR-200b and miR-200c predominantly function as tumor suppressors in BC by inhibiting cell proliferation and promoting apoptosis. Yao et al (80) demonstrated that miR-200a directly targets TFAM, inhibiting its protein expression and thereby consequently BC cell proliferation. Additionally, FEN1, a critical DNA metabolism regulator involved in DNA replication, damage repair, and telomere maintenance, is closely associated with tumor proliferation (81,82). Studies indicated that FEN1 forms a FEN1/proliferating cell nuclear antigen (PCNA)/DNA methyltransferase 3a (DNMT3a) complex with PCNA and DNMT3a, suppressing miR-200a expression via DNMT3a-mediated methylation. FEN1 knockout significantly upregulated miR-200a, which then targeted and downregulated hepatocyte growth factor (MET) and EGFR, thereby inhibiting the PI3K/AKT and MAPK/ERK signaling pathways and ultimately reducing BC cell proliferation (31). Chrysophanol activated the NF-κB signaling pathway by upregulating miR-200b and downregulating JAZF1, inducing pyroptosis and apoptosis, thus significantly reducing BC cell viability (34). Additionally, LINC01140 promotes BC progression by competitively inhibiting miR-200b through sponge adsorption. Knockdown of LINC01140 increased miR-200b levels, reducing downstream DMD expression and suppressing cell proliferation (83). miR-200c inhibits tumor proliferation both in vitro and in vivo by directly targeting KRAS and subsequently suppressing the AKT and ERK signaling pathways (35). Notably, Jones et al (84) showed that miR-200c expression is downregulated in Claudin-low BC, a rare subtype of TNBC, and restoring its expression significantly inhibited tumor cell proliferation, colony formation and tumor growth in vivo (84).

It is noteworthy that miR-429 exhibits a dual role in BC. Zhang et al (36) reported that miR-429 suppresses cell proliferation by targeting fibronectin 1, thereby inhibiting the Wnt/β-catenin signaling pathway. Other studies demonstrated that vitamin E δ-tocotrienol exerts anticancer effects both in vitro and in vivo by upregulating miR-429, suppressing its target gene XIAP, and inducing apoptosis (85). Additionally, Bi et al (86) showed that LINC01234 is highly expressed in TNBC, and its knockdown upregulates miR-429, decreases SYNJ1 expression, inhibits cell proliferation, and promotes apoptosis. By contrast, Li et al (87) found that miR-429 is overexpressed in the TNBC cell line MDA-MB-468 and promotes tumor proliferation by degrading the tumor suppressor factor DLC1. The regulatory role of miR-141 is also context dependent in BC. Xu et al (37) reported that MALAT1 is overexpressed as an oncogene in TNBC and is further induced under hypoxic conditions. Overexpression of miR-141-3p suppresses the post-transcriptional MALAT1/HIF-1α signaling pathway, thereby inhibiting autophagy initiation and cell proliferation (37). However, another study identified that miR-141-3p promotes proliferation and inhibits apoptosis by targeting and downregulating RBMS3 (88).

In addition, members of the miR-200 family influence BC cell proliferation and by regulating cell cycle progression. Dysregulation of the Hippo signaling pathway has been reported to promote proliferation and inhibit apoptosis, with YAP1 acting as a key downstream effector. Wang et al (89) demonstrated that miR-200a directly targets YAP1, induces G0/G1 cell cycle arrest, and reverses the pro-proliferative effects of circ-0005273. Furthermore, Yao et al (90) found that miR-200b targets Sp1, leading to G2/M phase arrest, a reduction in S-phase cells, inhibition of proliferation, and induction of apoptosis. Elevated intracellular cAMP levels are known to induce cell cycle arrest and apoptosis (91). Zhang et al (92) demonstrated that miR-200c downregulates PDE7B, increases intracellular cAMP levels, elevates the proportion of cells in the G1 phase, and suppresses cell proliferation. Moreover, Li et al (93) demonstrated that miR-200b-5p and miR-429-5p downregulate LIMK1 and its substrate CFL1, inhibit cyclin D1/CDK4/CDK6 and cyclin E1/CDK2, and ultimately impair cell cycle progression. Nevertheless, studies focusing on miR-200 family-mediated cell cycle regulation in BC remain limited. Whether this family regulates the cell cycle through additional molecular mechanisms to promote BC progression requires further investigation.

It has been demonstrated that the TME, composed of cellular and non-cellular components, plays a pivotal regulatory role in BC progression (94). Among these components, the miR-200 family acts as an essential regulator, influencing TME remodeling through multiple targets and pathways (Table I). Sun et al (38) showed significantly reduced miR-200b/c expression in cancer-associated fibroblasts (CAFs), closely linked to their pro-tumorigenic properties. Restoration of miR-200b/c expression directly targets and decreases IKKβ, inhibiting NF-κB signaling. This process subsequently reduces expression and secretion of downstream effector PAI-1, diminishing the ability of CAFs to facilitate tumor cell EMT and invasion (38). Tang et al (32) revealed a TGF-β1-miR-200-DNMT3B regulatory axis that promotes tumor progression: TGF-β1 suppresses miR-200 (miR-200a/b/c and miR-141) expression in CAFs, alleviating their post-transcriptional inhibition of DNMT3B. Elevated DNMT3B promotes methylation of CpG islands in the miR-200 promoters, leading to stable epigenetic silencing. This self-sustaining positive feedback loop enables CAFs to maintain a persistently activated phenotype. Additionally, reduced miR-141 expression elevates its target gene TCF12, promoting CXCL12 secretion by CAFs. CXCL12 subsequently activates the c-Myc/Cyclin D1 pathway in tumor cells, enhancing BC progression (32). Conversely, Lin et al (95) reported that oxidative stress induces DNA demethylation of the miR-200c promoter in CAFs, significantly upregulating its expression. Highly expressed miR-200c reprograms CAFs toward a MET state via the miR-205-COMMD1-NFκB-HIF axis, inducing a senescent phenotype. These reprogrammed CAFs enhance cancer cell proliferation, apoptosis resistance and immune suppression through paracrine secretion of factors such as TGFB2, CCL5, PDGFA/B and lactate, ultimately promoting tumor progression (95).

In another crucial TME component, tumor-associated macrophages (TAMs), the miR-200 family similarly exerts significant regulatory effects. TAMs, abundant immune cells within the TME, can be classified based on activation status into antitumor M1 and pro-tumor M2 subtypes. Meng et al (96) demonstrated that miR-200c promotes M2-type TAM polarization by upregulating PAI-2, thereby accelerating TNBC metastasis; however, the detailed molecular mechanisms remain to be clarified. Raue et al (97) described another aspect of miR-200c function: Apoptotic tumor cells release miR-200c, which macrophages then internalize. Uptake of miR-200c suppresses migration-related gene expression in macrophages, reducing their recruitment to tumor sites (97). These findings illustrate the complex mechanisms by which the miR-200 family regulates BC progression by modulating various cellular components of the TME.

A major cause of BC treatment failure is the persistence of cancer stem cells (CSCs). CSCs drive tumor initiation, progression and resistance to treatment. Due to their unique self-renewal capacity and multipotent differentiation potential, CSCs not only directly contribute to tumor progression and metastasis but also mediate chemotherapy resistance through various molecular mechanisms (98). Previous studies demonstrated that the miR-200 family, as key epigenetic regulators, plays a crucial role in controlling the stemness and phenotypic plasticity of BC stem cells (BCSCs) (Table I). For example, Hsu et al (99) found that inhibition of the miRNA processing enzyme Dicer significantly reduces miR-200b expression, whereas transfection with miR-200b mimics decreases the expression of stemness-associated transcription factors (Oct-4, Nanog, SOX-2 and KLF4), thus inhibiting CSC properties. Moreover, miR-200b suppresses mammary spheroid formation and maintenance by directly targeting Suz12, ultimately impairing CSC proliferation (100). Similarly, Tang et al (101) confirmed that miR-200c expression is generally reduced in BC cells and BCSCs. Overexpression of miR-200c directly targets and suppresses Jagged1, ZEB1 and Bmi1, thereby inhibiting tumor-sphere formation in HER2⁺ BC cells and decreasing the proportion of CD44⁺CD24⁻ cells. Importantly, miR-200c-mediated inhibition of stemness significantly restores sensitivity to trastuzumab, suppressing tumor growth and metastasis (101). Additional studies indicate that miR-200c inhibits BCSC proliferation and tumorigenicity by targeting BMI1 (102). Notably, BCSCs exist in two plastic states: epithelial-like (ALDH⁺) and mesenchymal-like (CD24⁻CD44⁺). These states interconvert and possess distinct biological behaviors: Epithelial-like BCSCs exhibit higher proliferation potential, whereas mesenchymal-like BCSCs show stronger migratory and invasive abilities (103). Liu et al (39) clarified the molecular basis of this phenomenon, demonstrating that miR-200c/141 inhibits HIPK1 expression by directly binding its 3'UTR. HIPK1 downregulation reduces phosphorylation at β-catenin Ser552, suppressing Wnt/β-catenin signaling. This regulatory axis determines BCSC state transitions: High miR-200c/141 expression promotes epithelial-like (ALDH⁺) BCSCs, while low expression favors mesenchymal-like (CD24⁻CD44⁺) BCSCs. These results provide a theoretical basis for novel therapeutic strategies targeting tumor growth and metastasis, suggesting the miR-200c/141-HIPK1-β-catenin axis as a potential therapeutic target (39). Additionally, Lim et al (14) reported that immortalized human mammary epithelial cells can spontaneously transition from a non-stem cell to a stem-like phenotype, which strongly correlates with the absence of miR-200 family expression. Restoration of miR-200 family expression reverses stem-like properties and promotes differentiation toward an epithelial phenotype, highlighting the crucial role of that the miR-200 family in stem cell and non-stem cell state transitions (14).

Numerous studies highlight the significant diagnostic and classification roles of the miR-200 family in BC (Table II). However, expression patterns vary across research contexts. Xu et al (107) quantified expression levels of all the miR-200 family members in 99 pairs of BC tissues and adjacent normal tissues using quantitative PCR (qPCR). They observed significant downregulation of all miR-200 members in cancer tissues and found that miR-200 could effectively distinguish patients with and without lymph node metastasis (107). These findings support the miR-200 family as potential diagnostic biomarkers for BC. Inflammatory BC (IBC) is a rare yet highly aggressive subtype often misdiagnosed due to the lack of reliable molecular biomarkers. Fahim et al (108) analyzed miRNA expression in primary tumors of patients with IBC and non-IBC using miRNA PCR arrays. They found significant downregulation of miR-200b-3p, miR-200c-3p and miR-203a-3p, with significant upregulation of miR-181b-5p in IBC. Receiver Operating Characteristic (ROC) curves demonstrated that each miRNA individually distinguished patients with IBC from patients with non-IBC. Notably, combining miR-181b-5p, miR-200b-3p and miR-200c-3p significantly improved diagnostic accuracy [area under the curve (AUC)=0.897], indicating potential molecular diagnostic markers for this challenging subtype (108). Qiao et al (109) reported significantly decreased expression of miR-200c in serum exosomes from patients with BC. ROC analysis indicated that miR-200c effectively discriminated patients with BC from healthy controls (AUC=0.854). Combining miR-200c with CEA, CA125 and CA153 increased diagnostic accuracy to an AUC of 0.914 (109). However, discrepancies exist regarding miR-200 expression patterns in circulation. Khalil et al (110) used qPCR to analyze blood samples from 54 patients with non-metastatic BC (NMBC), 46 patients with MBC and 50 healthy controls. They observed significant overexpression of miR-200a in the serum of patients with BC, with higher levels in MBC compared with patients with NMBC. Further analysis showed that miR-200a distinguished between MBC and NMBC, achieving an AUC of 0.708 (110). Similarly, Papadaki et al (111) found significantly higher plasma expression of miR-200b and miR-200c in patients with MBC compared with early-stage patients. The diagnostic AUC for miR-200b alone was 0.720, improving to 0.797 when combined with miR-21, miR-190 and miR-200c, suggesting that circulating miRNAs reflect distinct tumor biological characteristics (111). Additionally, Braicu et al (112) analyzed The Cancer Genome Atlas data and found significant overexpression of miR-200b was in TNBC and DPBC (ER⁺, PR⁺ and HER2⁻) compared with normal breast tissue, consistent with clinical plasma measurements. miR-200b effectively discriminated patients with BC from healthy controls, achieving an AUC of 0.8772. Notably, the present study independently validated miR-200b expression consistency between tumor tissues and plasma samples (21 TNBC, 47 DPBC and 19 normal samples), providing robust evidence supporting miR-200b as a reliable liquid biopsy biomarker (112).

The miR-200 family also exhibits significant prognostic value in BC (Table III). Yao et al (90) analyzed miR-200b expression levels in 278 paired BC and adjacent normal tissues by qPCR, showing significant downregulation in BC tissues. Further analysis indicated that low miR-200b expression was closely associated with aggressive clinicopathological features (advanced TNM stage, ER-negative status and HER-2-positive status) and predicted poorer clinical outcomes (90). Similarly, Ye et al (113) found reduced miR-200b expression in BC tissues. Patients with lower miR-200b levels exhibited significantly decreased overall survival (OS) and disease-free survival (DFS) compared with those with higher expression (113). A total of ~70% of BCs are estrogen receptor-positive (luminal subtype), and endocrine therapy remains one of the most effective adjuvant treatments. However, recurrence occurs in up to 40% of patients. Amorim et al (114) demonstrated that low expression of miR-200b-3p correlated with shorter endocrine resistance-free survival and DFS. Combining miR-200b-3p with miR-182-5p further improved prognostic accuracy (114). However, when examining circulating miRNAs, the clinical significance of miR-200 family expression patterns differs. Two studies by Fischer et al (115,116) revealed that high baseline plasma miR-200 expression in MBC correlated positively with circulating tumor cell (CTC) positivity and predicted shorter OS and progression-free survival (PFS). Moreover, high baseline miR-429 levels specifically indicated an increased risk of early recurrence. Notably, dynamic miR-200 expression changes during treatment also held prognostic importance: Effective therapy significantly reduced miR-200a/b/141 levels, which rebounded upon disease progression. Patients maintaining high miR-200 expression after treatment experienced a 3-5-fold increase in early recurrence risk. These findings suggest that miR-200 family members could serve as liquid biopsy biomarkers for clinical prognosis and treatment monitoring, particularly when combined with CTC detection for identifying high-risk patients (115,116). Similarly, Madhavan et al (117) performed a multicohort study demonstrating that elevated plasma miR-200 levels correlated with poorer OS and PFS, surpassing the predictive power of CTC detection alone. Notably, high miR-200a/b/c expression predicted metastasis risk up to two years before clinical diagnosis (AUC= 0.82), highlighting its potential as an early surveillance biomarker (117). MBC typically carries a poor prognosis and primarily relies on chemotherapy; however, drug resistance frequently leads to treatment failure and disease progression. Shao et al (118) observed significantly higher plasma miR-200a levels were in patients with chemotherapy-resistant MBC compared with sensitive patients, with high expression correlating with advanced disease stage. ROC analysis confirmed the high accuracy (AUC=0.881) of plasma miR-200a in differentiating chemotherapy-resistant from sensitive cases, indicating its potential as a predictive biomarker for chemotherapy resistance in MBC (118). Navarro-Manzano et al (119) measured plasma miR-200c-3p levels in 28 healthy women, 42 patients with MBC and 171 patients with locally advanced BC (LABC) using qPCR. They found significantly elevated miR-200c-3p levels in LABC and MBC groups compared with healthy controls, with high expression associated with reduced OS (119).

Although the miR-200 family shows significant diagnostic and prognostic value in BC tissues and circulating samples, noteworthy differences in expression patterns exist between these two contexts. Most tissue-based studies indicate that miR-200 members are downregulated in BC tissues, exerting tumor-suppressive effects (90,107,108,113). Conversely, circulating miR-200 levels, particularly in plasma or serum from patients with MBC, are frequently upregulated, and high levels correlate with poorer prognosis (110,111,115-117,119). Several mechanisms may explain this discrepancy: (i) Active secretion and selective miRNA packaging: Tumor cells actively release miRNAs into extracellular vesicles, such as exosomes, influencing the TME or evading intracellular tumor-suppressive roles. For example, Liu et al (79) demonstrated that BC cells selectively load miR-200c into exosomes through a Rab1A-mediated mechanism, thus reducing intracellular miR-200c levels while increasing circulating miR-200c. This 'secretory escape' could explain elevated circulating miR-200 despite suppressed tissue expression (79). (ii) Tumor heterogeneity and molecular subtype variability: BC is highly heterogeneous, and miRNA expression and functions differ across molecular subtypes (for example, luminal, HER2-positive, TNBC) (120). (iii) Sample type and detection methodology differences: Tissue samples reflect localized miRNA expression, while circulating samples represent systemic average levels. Additionally, differences in detection platforms, RNA extraction methods and normalization strategies may contribute to observed discrepancies (121).

Despite expression inconsistencies, these differences carry valuable biological and clinical insights. Elevated circulating miR-200 may indicate active secretion by tumor cells, closely linked to metastatic behavior. Therefore, clinical applications should clearly differentiate between tissue-derived and circulating miRNAs. Tissue miR-200 may be more appropriate for assessing local tumor characteristics and identifying therapeutic targets. By contrast, circulating miR-200 serves as a non-invasive biomarker for dynamic monitoring, metastasis prediction and treatment efficacy evaluation. Future studies should further explore miR-200 expression dynamics across sample types and its specific relationships with tumor biology to advance precision clinical applications.