Noncoding RNAs, Vital Players in Breast Cancer Metastasis

Yujuan Kang; Xingmiao Wang; Yanqing Liu; Jianqiao Cao; Jun Lin; Guangdong Qiao

doi:10.2147/BCTT.S556045

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Review

Noncoding RNAs, Vital Players in Breast Cancer Metastasis

Authors Kang Y , Wang X, Liu Y, Cao J, Lin J, Qiao G

Received 24 July 2025

Accepted for publication 25 November 2025

Published 30 December 2025 Volume 2025:17 Pages 1463—1492

DOI https://doi.org/10.2147/BCTT.S556045

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Robert Clarke

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Yujuan Kang,^* Xingmiao Wang,^* Yanqing Liu,^* Jianqiao Cao,^* Jun Lin, Guangdong Qiao

Department of Breast Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jun Lin, Department of Breast Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, People’s Republic of China, Email [email protected] Guangdong Qiao, Department of Breast Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, People’s Republic of China, Email [email protected]

Abstract: Breast cancer (BC) is the most common cause of deaths. Although recent medical advancements have improved survival of BC patients, the occurrence of metastasis increases mortality rate. Noncoding RNAs (ncRNAs) play important roles in BC metastasis (BCM). However, a detailed summary of ncRNAs involved in BCM is unavailable. Therefore, this review summarizes the key biological steps involved in BCM. We discussed the ncRNAs related to BCM according to “seed and soil” theory from four perspectives: (i) ncRNAs that make “breast cancer seed” preferable for BCM; (ii) ncRNAs that make “breast cancer seed” difficult for BCM; (iii) ncRNAs that make “breast cancer soil” preferable for BCM; (iv) ncRNAs that make “breast cancer soil” difficult for BCM. Lastly, we listed the ncRNAs and coding genes involved in BCM that act as initiators or suppressors. This review comprehensively overviews the biological mechanisms underlying BCM. The compiled evidence highlights the role of BCM-associated ncRNAs, which may serve as promising therapeutic targets for BCM.

Keywords: breast cancer, metastasis, noncoding RNAs, EMT, miRNA, circRNA

Introduction

BC is a major cause of cancer-related deaths.^1,2 It is characterized by molecular heterogeneity,^3,4 and the majority of deaths are associated with metastatic progression.⁵ Although advances have been made in treatment modalities, BCM remains the primary factor contributing to poor outcomes.⁶ All molecular types of BC are determined by the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).⁷ Triple-negative breast cancer (TNBC), characterized by the lack of ER, PR, and HER2 expression.^8,9 The most common locations of MBC include the bone, lungs, liver and brain.¹⁰ The pattern of distant metastasis may vary depending on the patient’s age and disease stage at diagnosis.^11,12 BC brain metastasis (BCBM) represents a severe clinical complication.¹³ Metastasis processes typically¹⁴ involve migration into adjacent tissues, adaptation to the new biological setting, cellular multiplication, and stimulation of blood vessel formation while avoiding programmed cell termination or defensive reactions from the immune system.¹⁵ Metastatic progression is driven by epithelial-mesenchymal transition (EMT).^16,17 EMT consists of the transformation of epithelial cells into mesenchymal-like cells, along with changes in shape and function that increase their invasive abilities.^18,19 Stem cells possess the dual capacity to maintain their population via self-replication while producing specialized tissue-specific cells through cellular maturation.²⁰ BC stem cells (BCSCs) control BCM.²¹ The highly tumorigenic properties of stem cells are associated with BCM.²² The tumor microenvironment (TME), mainly consisting of cellular components and release agents such as cytokines and chemokines, stimulates metastasis.^23,24 Extracellular matrix (ECM) was destroyed by matrix metalloproteinases (MMPs).²⁵

About 75% of the genetic material is transcribed into RNA, but only around 3% encodes messenger RNAs (mRNAs),²⁶ while the rest of the transcripts encode ncRNAs.²⁷ The main types of ncRNAs include long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and PIWI-interacting RNAs (piRNAs).²⁸ LncRNAs are transcripts longer than 200 nucleotides (nt)²⁹ usually produced by RNA polymerase II and modified after transcription, resulting in multiple forms.^30,31 These molecules involve different functions: epigenetic modifications, controlling transcription, post-transcription, and translation. The competing endogenous RNA (ceRNA) hypothesis, first introduced in 2011.³² It proposes that RNAs sharing microRNA response elements can compete for microRNA binding, affecting the availability of miRNAs and their target mRNAs.³³ Interestingly, some lncRNAs can produce functional peptides.^34–37 CircRNAs have closed-loop structures and lack 5′ caps and 3′ poly(A) tails.³⁸ They are categorized into exonic, intronic, and exon-intron circRNAs.³⁹ Moreover, miRNAs are short ncRNAs that control gene expression by interacting with 3′ untranslated regions (3′-UTRs) of target mRNAs.^40,41 PiRNAs exhibit marginally greater lengths (24–31 nt), originating from single-stranded precursor molecules transcribed from genomic areas known as piRNA clusters.^42,43

However, no studies have summarized the related ncRNAs that play vital roles in BCM. Herein, we summarize the key biological steps of BCM from two perspectives: Tumor cells and TME. Secondly, we summarized ncRNAs that function as BCM-promoting and BCM-inhibiting ncRNAs from the following four perspectives: (i) ncRNAs that make “breast cancer seed” preferable for BCM; (ii) ncRNAs that make “breast cancer seed” difficult for BCM; (iii) ncRNAs that make “breast cancer soil” preferable for BCM; (iv) ncRNAs that make “breast cancer soil” difficult for BCM. Finally, we summarized the ncRNAs and coding genes in BCM, and reviewed the related clinical trials and targeted medicines. This review offers an intuitive display of the landscape of ncRNAs involved in BCM. This review sheds light on the new directions for future BCM therapies.

BCM Mechanisms

Malignant cells proliferate at their original location, then penetrate the ECM and enter the bloodstream, subsequently migrating to distant tissues where they establish secondary growths.⁴⁴ A hypothesis emphasized the crucial interplay between mobile tumor cells (“seeds”) and the organ microenvironments (“soil” or TME) was purposed by Stephen Paget.⁴⁵ Metastasis depends on tumor cells (seed) and TME (soil).^46,47 The TME can be divided into cellular, soluble, and physical components.⁴⁸ In BC, TME comprises a network of cellular populations, including carcinoma-associated fibroblasts (CAFs), various immune cell subsets, pericytes, adipocytes, endothelial cells, and bone marrow-derived cells.^49–51 Besides cellular mediators, the TME contains multiple non-cellular (soluble mediators), ie, chemokines, growth factors, cytokines, and MMPs, and insoluble factors, ie, exosomes and the ECM.⁵² CAFs are crucial abundant stromal cell types within TME.⁵³ These fibroblasts are actively involved in the formation and rejuvenation of the ECM,⁵⁴ and they contribute to ECM degradation through the secretion of proteolytic enzymes (MMPs and urokinase-type plasminogen activators).^55,56 CAFs induce tumor metastasis through multiple mechanisms, such as the release of paracrine signaling molecules, ECM deposition and restructuring, and induction of metabolic changes within TME.^57,58 Tumor-associated macrophages (TAMs) exert pro-tumorigenic functions.^59,60 M1 and M2 macrophages occupying opposing ends.^61,62 Classically activated M1 macrophages was activated by interferon-γ and tumor necrosis factor (TNF). They display anticancer properties by secreting inflammatory mediators (TNF and interleukin-2 [IL-2]) along with reactive nitrogen and oxygen species.^63,64 Conversely, alternatively activated M2 macrophages respond to IL-4, IL-10, and IL-13, developing tumor-promoting biological behaviors.⁶⁴ BC is characterized by a large proportion of M2 phenotype.⁶⁵ M1/M2 macrophage polarization has tumor-promoting capabilities, including metastasis and immunosuppression.⁶⁶ Neutrophils have anti-tumorigenic (“N1”) and pro-tumorigenic (“N2”) phenotypes.⁶⁷ Extracellular vesicles (EVs) are divided into three types: exosomes (30–100 nm), apoptotic bodies (1000–5000 nm), and microvesicles (MVs; 100–1000 nm).⁶⁸ The proposed mechanisms and functional importance of BCM are shown in Figure 1 and Table 1.

Figure 1 The biological composition of breast cancer metastasis (BCM).

Table 1 The Components of the Breast Tumor Microenvironment (TME)

NcRNAs Involved in BCM

NcRNAs affect the behavior of tumor cells and TME involved in BCM. We summarized the ncRNAs involved in BCM: (i) ncRNAs that make “breast cancer seed” preferable for BCM; (ii) ncRNAs that make “breast cancer seed” difficult for BCM; (iii) ncRNAs that make “breast cancer soil” preferable for BCM; (iv) ncRNAs that make “breast cancer soil” difficult for BCM.

NcRNAs that Make “Breast Cancer Seed” Preferable for BCM

NcRNAs promote “breast cancer seed” preferable for BCM through various means to promote BC cell migration and invasion, EMT, angiogenesis, and BCSCs malignant behavior (Figures 2 and 3, Table 2).

Figure 2 Noncoding RNAs (ncRNAs) [microRNAs (miRNAs) excluded] that make “breast cancer seed” preferable for BCM.

Figure 3 MiRNAs that make “breast cancer seed” preferable for BCM.

Table 2 Noncoding RNAs (ncRNAs) That Make “Breast Cancer Seed” Preferable for Breast Cancer Metastasis (BCM)

LINC02273

HnRNPL-LINC02273 promotes BCM. HnRNPL-LINC02273 recruitment to the AGR2 promoter region upregulates AGR2 by augmenting H3K4me3 and H3K27ac expression.⁶⁹

LincIN

LincIN knockdown reduces lung metastasis. Elevated lincIN suppress p21 protein synthesis through translational inhibition, while reduced lincIN expression correlates with increased p21 abundance.⁷⁰

LncRNA CDC6

Overexpression of lncCDC6 has been shown to enhance migration. It acts as a ceRNA by interacting with miR‐215, thus preventing it from suppressing CDC6 mRNA.⁷¹

LncRNA ENST00000508435

LncRNAENST00000508435 substantially enhances migration. It directly interacts with FXR1, promoting BCM.⁷²

LncRNA TP73-AS1

TP73-AS1 enhanced ZEB1 levels through molecular competition, specifically by binding to miR-200a instead of allowing it to interact with the 3’-UTR region of ZEB1 mRNA.⁷³

LincRNA HOTAIR

HOTAIR promotes EMT lung metastasis.⁷⁴ Elevated HOTAIR in malignant epithelial cells alter the genomic distribution patterns of polycomb repressive complex 2 (PRC2), while promoting tumor dissemination.⁷⁵

Linc-ROR

Linc-ROR enhances BC migration and invasion. Linc-ROR functions as a ceRNA of miR-205. Linc-ROR prevents miR-205 target gene (ZEB2) degradation.⁷⁶

LncRNA OIP5-AS1

LncRNA OIP5‑AS1 facilitates BCM by sponging miR‑340‑5p to enhance the ZEB2 mRNA transcription.⁷⁷

LncATB

LncATB enhances EMT and migration. This molecule sequestered miR-200 cluster members while upregulating Twist1 transcription.⁷⁸ SIX-1 promotes lncATB transcription, which plays a pro-metastatic role by directly interacting with miR-200c to promote BCM.⁷⁹

LncRNA OR3A4

LncRNA OR3A4 was overexpressed in BC. OR3A4 silencing suppressed BC cell proliferation by repressing metastasis via EMT.⁸⁰

Lnc-408

Lnc-408 acts as a ceRNA by sponging miR-654-5p, thus increasing LIMK1 levels. Overexpression of Lnc-408 increases LIMK1 levels, therefore enhancing the invasive potential of BC cells.⁸¹

LncRNA NEAT1

LncRNA NEAT1 promotes EMT. A bidirectional inhibitory relationship between NEAT1 and miR-211 was discovered. Studies identified HMGA2, a known EMT promoter, as directly regulated by miR-211.⁸²

LncRNA PVT1

LncRNA PVT1 promotes EMT and BCM. It elevates FOXQ1 expression through the suppression of miR-128-3p and interacts with UPF1.⁸³

LncRNA AC073352.1

LncRNA AC073352.1 promotes BC cell invasive behavior, contributing to BCM by directly interacting with YBX1.⁸⁴

Linc-ZNF469-3

Linc-ZNF469-3 enhances lung metastasis. Mechanistically, it interacts with miR-574-5p, and restoring miR-574-5p levels decreases ZEB1 level.⁸⁵

LncRNA miR210HG

LncRNA miR210HG involved in promoting BCM. It acts as a ceRNA, sequestering miR-1226-3p and thus increasing the level of mucin 1.⁸⁶

LncRNA RAB11B-AS1

RAB11B-AS1 promotes metastatic potential by upregulating angiogenesis. Under hypoxic conditions, it increases the expression of vascular endothelial growth factor A (VEGFA) and angiopoietin-like 4 (ANGPTL4).⁸⁷

LncRNA SNHG1

SNHG1 contributes to metastasis through the HIF-1α/SNHG1/miR-199a-3p/ mitochondrial transcription factor A (TFAM) signaling axis. It downregulates miR-199a-3p and simultaneously upregulates TFAM, supporting metastatic under hypoxic conditions.⁸⁸

LncRNA NR2F1-AS1

LncRNA NR2F1-AS1 promotes BC angiogenesis. LncRNA NR2F1 sponges miR-338-3p to induce IGF-1, further activating the IGF-1R and ERK pathway.⁸⁹

LINC00511

LINC00511 regulates MMP13 expression by sponging miR-150, promoting cell migration.⁹⁰

LncRNA AU021063

IL-6 induces the level of lncRNA AU021063. AU021063 promotes BCM by stabilizing Trib3 and stimulating the Mek/Erk signaling pathway.⁹¹

LINC02163

LINC02163 knockdown inhibits migration. LINC02163 is a ceRNA of miR-511-3p and upregulates HMGA2 expression.⁹²

LncRNA TROJAN

LncRNA TROJAN promotes invasion. TROJAN interacts with ZMYND8, accelerating its proteasomal breakdown via competitive displacement of ZNF592.⁹³

LINC00518

LINC00518 induces CDX2 methylation by recruiting DNA methyltransferases, stimulating Wnt signaling pathway. Suppression of LINC00518 attenuates invasion and EMT.⁹⁴

LncRNA LUCAT1

LUCAT1 was overexpressed in BCSCs. LUCAT1 promotes BCSC proliferation. miR-5582-3p directly binds to LUCAT1 and TCF7L2 and adversely regulates their level.⁹⁵

CircFOXK2

CircFOXK2 is overexpressed in MBC. Its pro-metastatic function is related to regulating IGF2BP3 and miR-370.⁹⁶

Circ_RPPH1

circRPPH1 enhances metastatic potential in BC by functioning as a ceRNA for miR-146b-3p, leading to E2F2 upregulation.⁹⁷

CircANKS1B

CircANKS1B enhances BC invasion and EMT. It functions as a molecular sponge for miR-152-3p and miR-148a-3p, thus increasing USF1. USF1 induces transforming growth factor β1 (TGF-β1) transcription, stimulating the TGF-β1/Smad signaling cascade, which drives EMT.⁹⁸

Circ-EIF6

Circ-EIF6 induces metastasis and encodes a new peptide, EIF6-224aa. This peptide binds to MYH9, inhibits its degradation, and stimulates the Wnt/β-catenin signaling pathway.⁹⁹

miR-200a

miR-200a enhances BCM. Yes-associated protein 1 (YAP1) has been identified as a target of miR-200a. Its knockdown replicates the pro-metastatic effects observed with miR-200a overexpression, whereas YAP1 restoration reverses these effects in miR-200a-overexpressing BC cells.¹⁰⁰

miR-330-3p

Elevated level of miR-330-3p in BC cells enhances their invasive capacity. CCBE1 has been detected as a target of miR-330-3p.¹⁰¹

miR-191/425

Overexpression of miR-191 or miR-425 promotes BC migration, relying on the miR-191/425-induced DICER1 suppression.¹⁰²

miR-5694

miR-5694 binds to the 3′-UTR of AF9 mRNA, destabilizing it. AF9 interacts with Snail to suppress its transcriptional activity and facilitates the recruitment of CBP or GCN5, thus establishing an active chromatin state at the promoters of EMT-associated genes.¹⁰³

miR-615-3p

miR-615-3p enhances lung metastasis. miR-615-3p targets the 3′-UTR of PICK1, resulting in the increased TGF-β type I receptor (TGFBRI).¹⁰⁴

miR-182

TGF-β stimulates the expression of miR-182, which inhibits SMAD7. Elevated levels of miR-182 promote invasion and enhance TGF-β-induced osteoclastogenesis, contributing to bone metastasis.¹⁰⁵

miR-29a

miR-29a promotes lung metastasis. PTEN serves as a primary miR-29a-regulated gene, triggering EMT through activation of AKT pathway signaling.¹⁰⁶

miR-183

miR-183 facilitate migration and invasion depending on the existence of SIN3A, and ectopic miR-183 promotes BCM.¹⁰⁷

miR-10b

Twist-induced miR-10b inhibited the translation of mRNA encoding homeobox D10, leading to increased RHOC levels.¹⁰⁸

miR-4443

miR-4443 promotes BCM through tissue metalloproteinase 2 (TIMP2) suppression and MMPs activation. Coordinated TIMP2 reduction and MMP2 elevation following miR-4443 overexpression, establishing a mechanistic link to liver metastasis.¹⁰⁹

miR-7641

miR-7641 promotes BCM, with its biological effects transmitted to target cells through exosomal transfer mechanisms.¹¹⁰

NcRNAs that Make “Breast Cancer Seed” Difficult for BCM

NcRNAs promote “breast cancer seed” difficult for BCM by various means, including inhibiting BC cell migration and invasion ability, EMT, and BCSC malignant behavior (Figure 4 and Table 3).

Figure 4 NcRNAs that make “breast cancer seed” difficult for BCM.

Table 3 NcRNAs That Make “Breast Cancer Seed” Difficult for BCM

LncRNA NKILA

Low NKILA is associated with BCM. NKILA, transcriptionally activated by nuclear factor kappa B (NF-κB), interacts with the NF-κB/IκB complex and physically obstructs critical phosphorylation sites on IκB. This molecular interference prevents the phosphorylation of IκB by IKK, suppressing NF-κB signaling.¹¹¹

LINC00926

PGK1 mediates glycolysis.¹¹² LINC00926 inhibits BCM by inhibiting PGK1 expression.¹¹³

LncRNA MALAT1

MALAT1 inhibits BCM. MALAT1 interacts with the TEAD, effectively blocking its ability to form complexes with YAP.¹¹⁴

LncRNA-CTD-2108O9.1

LncRNA-CTD-2108O9.1 is a BCM inhibitor targeting the leukemia inhibitory factor receptor (LIFR), a BCM suppressor.¹¹⁵

LncRNA TUSC8

Silencing TUSC8 promotes BC cell migration. TUSC8 acts as a ceRNA for myosin regulatory light chain interacting protein (MYLIP) by sequestering miR-190b-5p, thus modulating the level of EMT-related markers and inhibiting BCM.¹¹⁶

LncRNA MEG3

MEG3 suppresses invasion. MEG3 inhibits miR-421 and E-cadherin expression by acting as a ceRNA, which could sponge miR-421.¹¹⁷

LncRNA AC073284.4

AC073284.4 functions as a molecular sponge for miR-18b-5p, thus enhancing the expression of dedicator of cytokinesis protein 4 (DOCK4). This regulatory interaction suppresses invasion, metastasis, and EMT.¹¹⁸

LncRNA NLIPMT

LncRNA NLIPMT inhibits cell motility. Glycogen synthase kinase 3β (GSK3β) is a targeted protein regulated by lncNLIPMT.¹¹⁹

CircNOL10

CircNOL10 suppresses EMT by acting as a molecular sponge for miR-767-5p. This interaction elevates suppressor of cytokine signaling 2 (SOCS2) and suppresses the JAK2/STAT5 signaling axis.¹²⁰

miR-328-3p

miR-328-3pmiR-328-3p-CPT1A-FAO axis involved in BCM. miR-328-3p upregulation or interruption of this axis can be exploited to develop efficient strategies to decrease metastasismiR-328-3p.¹²¹

miR-290

miR-290 exerts its tumor-suppressive function by targeting Arid4b, promoting apoptotic pathways, ultimately inhibiting BC progression.¹²²

miR-29b-2/miR-338

Overexpression of miR-29b-2 and miR-338 inhibits EMT. miR-29b-2 targets VEGFA, while miR-338 suppresses NRP1. These regulatory interactions mediate the inhibitory effect of FOXO3a on the VEGFA/NRP1 signaling axis, to reduce metastatic potential.¹²³

miR-146a/b

BCM suppressor 1 (BRMS1) reduces BCM.^124,125 BRMS1 upregulates the expression of miR-146a and miR-146b. These microRNAs suppress EGFR signaling, thus inhibiting BCM.¹²⁶

miR-409-3p

miR-409-3p overexpression impairs BC cell migration and invasion. miR-409-3p interacts with the 3′-UTR of ZEB1.¹²⁷

miR-421

miR-421 suppresses BCM. miR-421 suppress the 3′-UTR of metastasis-associated 1 (MTA1), and miR-421 suppresses BCM by inhibiting MTA1.¹²⁸

miR-133b

miR-133b is a tumor suppressor. Downregulated miR-133b levels participate in BC progression by targeting Sox9, which regulates BCM.¹²⁹

miR-33a

miR-33a overexpression decreases cell invasion and inhibits lung metastasis. ADAM9 and ROS1 are directly regulated by miR-33a.¹³⁰

miR-361-5p

miR-361-5p suppresses BCM. Fibroblast growth factor receptor 1 (FGFR1) is a miR-361-5p target. Moreover, miR-361-5p inhibits invasion and metastasis by targeting MMP1.¹³¹

miR-515-5p

miR-515-5p inhibits MARK4 through direct 3′-UTR interaction involving migration. miR-515-5p/MARK4 signaling inhibits metastasis.¹³²

miR-190

miR-190 inhibits BCM by directly targeting SMAD2.¹³³

miR-200c

miR-200c impedes invasive ability by targeting ZNF217, a transcriptional enhancer of TGF-β and ZEB1, a downstream effector within the TGF-β signaling axis. miR-200c/ZEB1 and miR-200c/ZNF217/TGF-β/ZEB1 interactions that facilitate metastasis.¹³⁴

miR-135b-5p

Syndecan-binding protein (SDCBP) has been identified as a downstream effector of miR-135b-5p. Suppression of miR-135b-5p is correlated with enhanced EMT and increased invasion.¹³⁵

miR-760

miR-760 suppresses the BC stem cell population by inactivating the NANOG, thus restraining metastatic progression.¹³⁶

miR-93

Elevated level of miR-93 suppresses invasiveness and metastatic potential. Wiskott-Aldrich syndrome protein family member 3 (WASF3), a key modulator of cytoskeletal reorganization and CSC characteristics, is a direct target of miR-93.¹³⁷

miR-149

miR-149 plays an anti-metastatic role by negatively regulating G protein-coupled receptor kinase-interacting protein 1 (GIT1). miR-149 also disrupts fibronectin-induced focal adhesion assembly, an effect that can be reversed through the restoration of GIT1.¹³⁸

miR-7

miR-7 is downregulated in BCSCs. It inhibits invasion and metastatic behavior, reduces the BCSC population, and partially counteracts EMT by directly targeting the SETDB1.¹³⁹

miR-519d

miR-519d overexpression suppresses migration. MMP3 is a direct target of miR-519d.¹⁴⁰

miR-203

miR-203 inhibits BC invasion. Furthermore, miR-203 demonstrates anti-metastatic properties by significantly reducing the production of MMP2, MMP7, and MMP9.¹⁴¹

miR-1

miR-1 acts as a tumor suppressor by targeting KRAS and MALAT1. Restoration of miR-1 suppresses metastasis.¹⁴²

miR-30a-5p

miR-30a-5p negatively regulates LDHA by targeting its 3′-UTR. By suppressing LDHA-mediated glycolysis, miR-30a-5p attenuates BCM.¹⁴³

miR-133a-3p

miR-133a-3p is epigenetically silenced due to DNA hypermethylation. Mastermind-like transcriptional co-activator 1 (MAML1) has been identified as a direct target of miR-133a-3p.¹⁴⁴

miR-204-5p

miR-204-5p acts as a tumor suppressor and is involved in BCM progression. It directly targets PIK3CB and modulates downstream PI3K/Akt signaling pathways.¹⁴⁵

NcRNAs that Make “Breast Cancer Soil” Preferable for BCM

NcRNAs promote “breast cancer soil” preferred for BCM by various means to promote M2 macrophage polarization, CAF signaling pathway, and N2 conversion (Figure 5 and Table 4).

Figure 5 NcRNAs that make “breast cancer soil” preferable for BCM.

Table 4 NcRNAs That Make “Breast Cancer Soil” Preferable and Difficult for BCM

LncRNA SNHG1

SNHG1 acts as a regulatory factor in M2 macrophage polarization. Its knockdown suppresses M2 polarization by inhibiting STAT6 phosphorylation and impairs the migratory ability.¹⁴⁶

LncRNA SNHG5

SNHG5 is overexpressed in CAFs and plays a critical role in premetastatic niche formation by promoting angiogenesis. SNHG5 interacts with IGF2BP2, stabilizing ZNF281 mRNA. The upregulation of ZNF281 transcriptionally enhances CCL2 and CCL5, activating the P38 MAPK signaling cascade.¹⁴⁷

Linc00514

Linc00514 promotes lung metastasis. Linc00514 increases the population of M2-polarized macrophages. Linc00514 upregulates Jagged1 by facilitating STAT3 phosphorylation, thus activating the Jagged1-mediated Notch. This activation elevated secretion of IL-4 and IL-6, and M2 macrophage polarization.¹⁴⁸

LncRNA PTH-AS

LncRNA PTH-AS enhances invasion and lung metastasis. PTH-AS demonstrate elevated macrophage infiltration, accelerating angiogenesis.¹⁴⁹

LincRNA-p21

LincRNA-p21 is highly expressed in macrophages. Its silencing promotes macrophage polarization toward the M1 phenotype, a process driven by MDM2-mediated proteasomal degradation of p53 and activating NF-κB and STAT3.¹⁵⁰

Lin28B

Lin28B promotes an immunosuppressive pre-metastatic environment by stimulating neutrophil penetration and polarization toward the N2 phenotype, mediated by tumor-derived exosomes with reduced let-7s levels. It has been shown to facilitate BCM by modulating immune suppression within the metastatic lung microenvironment.¹⁵¹

LncRNA NR_109

NR_109 induces macrophage polarization toward an M2-like phenotype and participates in a positive feedback loop involving NR_109, FUBP1, and c-Myc, which drives its role in shaping a pro-tumorigenic TME.¹⁵²

Circ_0001142

Endoplasmic reticulum stress facilitates exosome release and promotes the transfer of circ_0001142 into macrophages, thus modulating their polarization. Circ_0001142/miR-361-3p/PIK3CB axis is pivotal in controlling macrophage polarization.¹⁵³

CircTBPL1

Exosomal circTBPL1, derived from CAFs, enhances migration. Mechanistically, circTBPL1 protects TPBG from miR-653-5p–mediated degradation. The CAF-derived exosomal circTBPL1/miR-653-5p/TPBG regulatory axis is crucial in BC advancement.¹⁵⁴

CircRNA cSERPINE2

CircRNA cSERPINE2 is elevated in BC. Exosomal cSERPINE2 shuttles TAMs and enhances IL-6 secretion and invasion. Furthermore, IL-6 elevates intracellular concentrations of EIF4A3 and CCL2, thus amplifying cSERPINE2 production while simultaneously promoting macrophage infiltration.¹⁵⁵

CircWWC3

CircWWC3 elevates IL-4 levels. The increased of IL-4 enhances the macrophages’ polarization into an M2-like phenotype within the TME, thus promoting migration.¹⁵⁶

miR-500a-5p

miR-500a-5p is found at high levels in BC cells after treatment with exosomes released by CAFs. miR-500a-5p is passed from CAFs to BC cells, promoting metastasis by interacting with ubiquitin-specific peptidase 28 (USP28).¹⁵⁷

miR-18b

miR-18b is elevated in exosomes secreted by CAFs, and exosomal miR-18b accelerates the metastatic behavior by targeting the 3′-UTR of transcription elongation factor A like 7 (TCEAL7). The miR-18b-TCEAL7 signaling enhances the nuclear translocation of Snail by activating the NF-κB pathway, consequently initiating EMT.¹⁵⁸

miR-222

miR-222 is increased in CAFs relative to normal fibroblasts (NFs). Lamin B receptor (LBR) is a target of miR-222 and is involved in fibroblast reprogramming. Both miR-222 overexpression and LBR depletion convert NFs into a CAF-like phenotype.¹⁵⁹

miR-9

miR-9, which is upregulated in BC cell. Tumor-derived miR-9 is transferred to NFs via exosomes, inducing their reprogramming into CAFs. NFs transiently transfected with miR-9 revealed altered expression of genes primarily involved in cell motility and ECM regeneration.¹⁶⁰

miR-181a

Exosomal miR-181a, transferred by monocytes activated through interaction with CAFs, contributes to BC progression by partially activating the Akt.⁶⁵

miR-19a

ER⁺ BC cells actively secrete high levels of exosomal miR-19a and integrin-binding sialoprotein (IBSP). IBSP establishes an osteoclast-rich microenvironment. This environment facilitates the targeted delivery of exosomal miR-19a to osteoclasts, thus promoting osteoclastogenesis.¹⁶¹

miR-1910-3p

Exosomes transfer miR-1910-3p to BC cells, inhibit myotubularin-related protein 3 expression (MTMR3), and activate the NF-κB and wnt/β-catenin, promoting BCM.¹⁶²

miR-3613-3p

miR-3613-3p upregulation has been observed in CAF-secreted exosomes. Exosomal miR-3613-3p accelerates metastatic potential, whereas its downregulation in CAF-derived exosomes suppresses BCM by affecting SOCS2.¹⁶³

miR-138-5p

Exosomal miR-138-5p promotes M2 polarization of macrophages by downregulating KDM6B. Macrophages exposed to exosomal miR-138-5p promote lung metastasis.¹⁶⁴

miR-122

miR-122 promotes metastatic progression. miR-122 disrupts glucose processing in target niche cells through downregulation of pyruvate kinase, a pivotal enzyme in glycolysis.¹⁶⁵

miR-105

Increased miR-105 are involved in metastasis. Therapeutic inhibition of miR-105 demonstrates potent suppression of metastatic progression.¹⁶⁶

miR-182

miR-182 promotes TAM polarization toward the M2 phenotype. miR-182 further downregulates TLR4, thus inactivating NF-κB signaling and enhancing M2 polarization of TAMs.¹⁶⁷

miR-200c

miR-200c/PAI-2 axis contributes to BCM by stimulating alternative activation of TAMs. This axis promotes M2 polarization via induction of IL-10 expression.¹⁶⁸

NcRNAs that Make “Breast Cancer Soil” Difficult for BCM

NcRNAs promote “breast cancer soil” difficult for BCM by various means to inhibit M2 macrophage polarization (Table 4).

miR-382

Tumor cells suppress miR-382 in TAMs, leading to the inhibition of the target PGC-1α. The upregulation of PGC-1α alters the metabolic profile of TAMs, promoting their polarization into the M2 phenotype. These M2-polarized TAMs secrete TGF-β and IL-10, facilitating EMT and enhancing metastatic progression.¹⁶⁹

miR-17/20

miR-17/20 is downregulated in BC. miR-17/20 directly targets the 3′-UTR of IL-8 mRNA, reducing IL-8 levels. miR-17/20 also downregulates cytokeratin 8 level via cyclin D1 modulation.¹⁷⁰

NcRNAs and Coding Genes Involved in BCM

NcRNAs are involved in BCM through various mechanisms. As previously described, some of these are black sheep that promote BCM, including LINC02273, LincIN, Lnc CDC6, ENST00000508435, LncTP73-AS1, LincRNA HOTAIR, Lnc-ROR, Lnc OIP5-AS1, LncATB, Lnc OR3A4, Lnc-408, Lnc NEAT1, LncPVT1, CircFOXK2, Circ_RPPH1, miR-200a, miR-330-3p and so on. NcRNAs that inhibit BCM include LncRNA NKILA, LINC00926, LncRNA MALAT1, LncRNA-CTD-2108O9.1, LncRNA TUSC8, LncRNA MEG3, LncRNA AC073284.4, LncRNA NLIPMT, CircNOL10, miR-290, miR-29b-2/miR-338, miR-146a/b and so on (Table 5).

Table 5 NcRNAs Involved in BCM

We reviewed these ncRNA related clinical trials, however, there are currently no clinical trials available. In the vast majority of cases, ncRNAs often targeting downstream coding genes for certain regulating purposes. Then we summarized studies provide us with a clear understanding of the coding genes involved in “breast cancer seed” related to BCM which include: AGR2; P21; CDC6; FXR1; ZEB1; PRC2; ZEB2; Twist1; SIX1; LIMK1; HMGA2; FOXQ1; YBX1; mucin 1; VEGFA/ANGPTL4; TFAM; IGF-1; MMP13; Trib3; ZNF592; CDX2; LUCAT1/TCF7L2; IGF2BP3; E2F2; USF1; MYH9; YAP1; CCBE1; DICER1; AF9; PICK1; SMAD7; PTEN; CPT1A; SIN3A; RHOC; TIMP2; NF-Kb; PGK1; TEAD; LIFR; MYLIP; E-cadherin; DOCK4; GSK3β; SOCS2/JAK2/STAT5; Arid4b; VEGFA/NRP1; EGFR; MTA1; Sox9; ADAM9/ROS1; FGFR1/MMP1; MARK4; SMAD2; SDCBP; NANOG; WASF3; GIT1; SETDB1; MMP3; MMP2/7/9; K-RAS/MALAT1; LDHA; MAML1 and PIK3CB. Then we summarized studies provide us with a clear understanding of the coding genes involved in “breast cancer soil” related to BCM which include: STAT6; ZNF281; Jagged1/STAT3; NF-Κb/STAT3; let-7s; FUBP1; PIK3CB; TPBG; IL-6; IL-4; USP28; TCEAL7; LBR; Akt; IBSP; MTMR3; SOCS2; KDM6B; TLR4; PAI-2; PGC-1α; IL-8 (Figure 6 and Table 6).

Figure 6 Coding genes involved in BCM.

Table 6 Coding Genes Involved in “Breast Cancer Seed and Soil” Related to BCM

We reviewed that the related clinical trials to these coding genes which include: JAK/STAT, mucin 1, VEGFA, IGF-1, GSK3β, EGFR, ROS1 and PIK3CB. The related targeted medicines in the clinical trials are as follows: JAK2 inhibitor: Ruxolitinib; STAT3 inhibitor: TTI-101 and silibinin; mucin 1 related vaccinia: Recombinant Vaccinia Virus That Expresses DF3/MUC1, HuMNC2-CAR44 CAR T cells or huMNC2-CAR22 CAR T cells, Recombinant vaccinia-MUC1 vaccine and so on; VEGFA inhibitor: BNT327, Aflibercept, Bevacizumab, BNT323, Apatinib, Lucitanib, erlotinib; IGF-1 inhibitor: [225Ac]-FPI-1434; GSK3β inhibitor: 9-ING-41; EGFR inhibitor: SCT200, TAS2940, Poziotinib, Lapatinib, SYS6010, AZD4547, Gefitinib; ROS1 inhibitor: Entrectinib, Taletrectinib; PIK3CB inhibitor: AZD8186 (Supplemental Table 1).

Conclusion

BC is the leading disease among women. Despite comprehensive treatment methods, metastasis still posing a serious threat to life. BCM is involved in various biological processes. The metastasis-related changes within the tumor play a vital role in BCM, but so do metastasis-related changes within the TME. NcRNAs play an indispensable role in the development of BCM. LncRNA, circRNA, and miRNAs are the primary ncRNAs that function through various mechanisms, including ceRNA and binding with other proteins and RNA. We first summarized the key biological steps of BCM from two perspectives: tumor cells and the TME. NcRNAs promote “breast cancer seed” preferable or difficult for BCM through various means to regulate BC cell migration and invasion, EMT procession, and BCSCs malignant behavior. NcRNAs promote “breast cancer soil” preferred or difficult for BCM by various means to promote M2 macrophage polarization, CAF signaling pathway, and N2 conversion. Certain ncRNAs, such as HOTAIR, can be involved in BCM through multiple mechanisms, and numerous ncRNAs can target the same downstream genes. For example, Lnc TP73-AS1 and Linc-ZNF469-3 can target ZEB1 to regulate BCM, and lncRNA NEAT1 and LINC02163 can target HMGA2 to regulate BCM. LncRNA SNHG1 promotes BC cells and TME preferred for BCM. Lastly, we summarized the coding-genes involved in BCM from two perspectives: tumor cells and TME. We reviewed these ncRNA related clinical trials, however, there are currently no clinical trials available. We reviewed that the related clinical trials and the medicines targeted these coding genes which include: JAK2-STAT3, mucin 1, VEGFA, IGF-1, GSK3β, EGFR, ROS1 and PIK3CB. A large number of targeted drugs have been introduced into clinical research.

Based on our article, it provides a new direction for inhibiting BCM in the future. Firstly, our future research could focus on upregulating the NcRNAs related to “breast cancer seed” difficult for BCM and “breast cancer soil” difficult for BCM; or downregulating NcRNAs related to “breast cancer seed” preferable for BCM and “breast cancer soil” preferred for BCM. In recent years, we noted that more and more researchers are committed to studying the reprogramming of TME. The reprogramming of TME include various aspects: metabolic, immune regulation, neutrophils, macrophage, CAFs and so on. In one word, our review provides novel therapeutic targets for improving the prognosis of BCM and highlights new avenues for future BCM therapies. In addition, what caught our attention was that VEGFA and EGFR having a large number of clinical trials and targeted drugs. According our review, ncRNA RAB11B-AS1 and miR-29b-2/miR-338 targeted VEGFA; miR-146a/b targeted EGFR. NcRNA RAB11B-AS1, miR-29b-2/miR-338/146a/b have the potential to be research subjects for the next clinical trial. Clinically, ncRNA cannot be used as a therapeutic target for breast cancer metastasis at present for lacking clinical trials. The biggest challenge is: clinically, it is difficult to obtain breast cancer samples, and its expression content in blood is low. It requires a large number of blood samples to detect the expression of ncRNA. In summary, our article provides research direction for future treatment of BCM.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Abbreviation

3′-UTR, 3′-untranslated regions; ANGPTL4, Angiopoietin-like 4; BC, Breast Cancer; BCM, Breast Cancer Metastasis; BCBM, BC brain metastasis; BCSCS, BC stem cells; BRMS1, BCM suppressor 1; CAFs, cancer-associated fibroblasts; ceRNA, competitive endogenous RNA; circRNA, circular RNA; ECM, Extracellular Matrix; ER, Estrogen Receptor; DOCK4, Dedicator of cytokinesis protein 4; EMT, Epithelial–mesenchymal transition; EVs, Extracellular vesicles; FGFR1, Fibroblast growth factor receptor 1; GIT1, G-protein-coupled receptor kinase-interacting protein 1; GSK3β, Glycogen synthase kinase 3β; HER2, Human Epidermal Growth Factor Receptor 2; IBSP, Integrin-Binding Sialoprotein; LBR, Lamin B receptor; LncRNA, Long noncoding RNA; LIFR, Leukemia Inhibitory Factor Receptor; MAML1, Mastermind-like transcriptional coactivator 1; miRNA, microRNA; MVs, Microvesicles; MMPs, matrix metalloproteinases; mRNAs, Message RNAs; MTA1, Metastasis Associated 1; MTMR3, Myotubularin-Related Protein 3; MYLIP, Myosin Regulatory Light Chain Interacting Protein; NcRNAs, Noncoding RNAs; NFs, Normal fibroblasts; NF-κB, Nuclear Factor Kappa B; nt, nucleotides; piRNA, PIWI interacting RNA; PR, Progesterone Receptor; PRC2, Polycomb Repressive Complex 2; SDCBP, Syndecan binding protein; SOCS2, Suppressors of Cytokine Signaling 2; TAM, Tumor-associated macrophages; TCEAL7, Transcription Elongation Factor A Like 7; TFAM, Mitochondrial Transcription Factor A; TIMP2, Tissue Inhibitors of Metalloproteinase 2; TGF-β1, Transforming Growth Factor β1; TGFBRI, TGF-β the type I Receptor; TME, Tumor Microenvironment; TNBC, Triple-Negative Breast Cancer; TNF, Tumor Necrosis Factor; USP28, Ubiquitin-specific peptidase 28; VEGFA, Vascular Endothelial Growth Factor A; WASF3, Wiskott-Aldrich syndrome protein family member 3; YAP1, Yes-associated protein 1.

Data Sharing Statement

No datasets were generated or analysed during the current study.

Acknowledgments

Acknowledgement all the authors.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was supported by the Beijing Vlove Charity Foundation (ky1322); Yantai Yuhuangding Hospital Youth Launch Fund (kj0521) and Yantai Yuhuangding Hospital Doctoral Research Launch Fund (kj0570).

Disclosure

The authors declare no competing interests.

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