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2000
Volume 14, Issue 2
  • ISSN: 2211-5366
  • E-ISSN: 2211-5374

Abstract

Introduction

Breast cancer (BC) is the most prevalent cancer among women globally. Metastasis is the leading cause of mortality in most cancers. Early BC detection before metastasis can enhance survival rates. Understanding BC metastasis mechanisms could aid in developing metastasis-specific treatments.

Methods

The role of long non-coding RNAs (lncRNA) in cancer progression is recognized, yet the importance of specific lncRNAs in BC, despite potential alterations, remains inadequately explored. We utilized bioinformatics tools to identify novel lncRNAs dysregulated in metastasis. To achieve this objective, the gene expression profile of GSE102484, encompassing metastatic and non-metastatic BC tissue samples, was analyzed using the limma package in R with cut-off criteria set at an adjusted p-value < 0.005 and |fold change (FC)| ≥ 0.5. We used WGCNA analysis to find co-expression genes for lncRNAs. Then, we identified hub genes and performed pathway enrichment to better understand the results. Considering the defined criteria, eight novels of dysregulated lncRNAs and top 10 miRNAs were identified.

Results

Dysregulated lncRNAs are found in yellow, green, brown, purple, and turquoise co-expression modules from WGCNA analysis. Enrichment analysis of these co-expressed modules revealed relevant pathways to metastasis, such as epithelial-to-mesenchymal transition and integrin cell-surface interactions, as well as regulation of HIF1-alpha. In addition, SDPR, TGFB1I1, ILF3, KIF4A, and COL5A1 were identified as hub genes. Based on DElncRNA-miRNA-DEmRNA connections and co-expression, we ultimately constructed lncRNA-associated ceRNA axes.

Conclusion

The current study may identify novel lncRNAs implicated in BC metastasis; still, additional research is required to determine the potential functions of these lncRNAs in BC metastasis.

© 2025 Bentham Science Publishers
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2025-12-18

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References

  1. HarbeckN. Penault-LlorcaF. CortesJ. Breast cancer.Nat. Rev. Dis. Primers2019516610.1038/s41572‑019‑0111‑231548545
     [Google Scholar]
  2. ArnoldM. MorganE. RumgayH. Current and future burden of breast cancer: Global statistics for 2020 and 2040.Breast202266152310.1016/j.breast.2022.08.01036084384
     [Google Scholar]
  3. Llombart-CussacA. CortésJ. ParéL. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial.Lancet Oncol.201718454555410.1016/S1470‑2045(17)30021‑928238593
     [Google Scholar]
  4. WaksA.G. WinerE.P. Breast Cancer Treatment.JAMA2019321328830010.1001/jama.2018.1932330667505
     [Google Scholar]
  5. MillerK.D. NogueiraL. MariottoA.B. Cancer treatment and survivorship statistics, 2019.CA Cancer J. Clin.201969536338510.3322/caac.2156531184787
     [Google Scholar]
  6. BaiJ. LiZ. GuoJ. Development of a predictive model to identify patients most likely to benefit from surgery in metastatic breast cancer.Sci. Rep.2023131384510.1038/s41598‑023‑30793‑836890157
     [Google Scholar]
  7. MalterW. HellmichM. BadianM. KirnV. MallmannP. KrämerS. Factors Predictive of Sentinel Lymph Node Involvement in Primary Breast Cancer.Anticancer Res.20183863657366210.21873/anticanres.1264229848724
     [Google Scholar]
  8. ServissJ.T. JohnssonP. GrandérD. An emerging role for long non-coding RNAs in cancer metastasis.Front. Genet.2014523410.3389/fgene.2014.0023425101115
     [Google Scholar]
  9. FaticaA. BozzoniI. Long non-coding RNAs: new players in cell differentiation and development.Nat. Rev. Genet.201415172110.1038/nrg360624296535
     [Google Scholar]
  10. FlynnR.A. ChangH.Y. Long noncoding RNAs in cell-fate programming and reprogramming.Cell Stem Cell201414675276110.1016/j.stem.2014.05.01424905165
     [Google Scholar]
  11. KazemzadehM. SafaralizadehR. OrangA.V. LncRNAs: emerging players in gene regulation and disease pathogenesis.J. Genet.201594477178410.1007/s12041‑015‑0561‑626690535
     [Google Scholar]
  12. DerrienT. JohnsonR. BussottiG. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression.Genome Res.20122291775178910.1101/gr.132159.11122955988
     [Google Scholar]
  13. GuptaR.A. ShahN. WangK.C. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.Nature201046472911071107610.1038/nature0897520393566
     [Google Scholar]
  14. GumireddyK. LiA. YanJ. Identification of a long non-coding RNA-associated RNP complex regulating metastasis at the translational step.EMBO J.201332202672268410.1038/emboj.2013.18823974796
     [Google Scholar]
  15. EadesG. WolfsonB. ZhangY. LiQ. YaoY. ZhouQ. lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.Mol. Cancer Res.201513233033810.1158/1541‑7786.MCR‑14‑025125253741
     [Google Scholar]
  16. XingZ. LinA. LiC. lncRNA directs cooperative epigenetic regulation downstream of chemokine signals.Cell201415951110112510.1016/j.cell.2014.10.01325416949
     [Google Scholar]
  17. IsmailN.H. MussaA. Al-KhreisatM.J. Dysregulation of Non-Coding RNAs: Roles of miRNAs and lncRNAs in the Pathogenesis of Multiple Myeloma.Noncoding RNA2023966810.3390/ncrna906006837987364
     [Google Scholar]
  18. GautierL. CopeL. BolstadB.M. IrizarryR.A. affy—analysis of Affymetrix GeneChip data at the probe level.Bioinformatics200420330731510.1093/bioinformatics/btg40514960456
     [Google Scholar]
  19. HeidarzadehpilehroodR. PirhoushiaranM. Binti OsmanM. Abdul HamidH. LingK.H. Weighted Gene Co-Expression Network Analysis (WGCNA) Discovered Novel Long Non-Coding RNAs for Polycystic Ovary Syndrome.Biomedicines202311251810.3390/biomedicines1102051836831054
     [Google Scholar]
  20. LangfelderP. HorvathS. WGCNA: an R package for weighted correlation network analysis.BMC Bioinformatics20089155910.1186/1471‑2105‑9‑55919114008
     [Google Scholar]
  21. D’haeseleerP. How does gene expression clustering work?Nat. Biotechnol.200523121499150110.1038/nbt1205‑149916333293
     [Google Scholar]
  22. OvensK. EamesB.F. McQuillanI. Comparative Analyses of Gene Co-expression Networks: Implementations and Applications in the Study of Evolution.Front. Genet.20211269539910.3389/fgene.2021.69539934484293
     [Google Scholar]
  23. PathanM. KeerthikumarS. AngC.S. FunRich: An open access standalone functional enrichment and interaction network analysis tool.Proteomics201515152597260110.1002/pmic.20140051525921073
     [Google Scholar]
  24. OtasekD. MorrisJ.H. BouçasJ. PicoA.R. DemchakB. Cytoscape Automation: Empowering workflow-based network analysis.Genome Biol.201920118510.1186/s13059‑019‑1758‑431477170
     [Google Scholar]
  25. ChinC.H. ChenS.H. WuH.H. HoC.W. KoM.T. LinC.Y. cytoHubba: identifying hub objects and sub-networks from complex interactome.BMC Syst. Biol.20148S4Suppl. 4S1110.1186/1752‑0509‑8‑S4‑S1125521941
     [Google Scholar]
  26. YousefniaS. Seyed ForootanF. Seyed ForootanS. Nasr EsfahaniM.H. GureA.O. GhaediK. Mechanistic pathways of malignancy in breast cancer stem cells.Front. Oncol.20201045210.3389/fonc.2020.0045232426267
     [Google Scholar]
  27. ApostolouP. PapasotiriouI. Current perspectives on CHEK2 mutations in breast cancer.Breast Cancer (Dove Med. Press)2017933133510.2147/BCTT.S11139428553140
     [Google Scholar]
  28. GodetI. GilkesD.M. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer.Integr. Cancer Sci. Ther.20174110.15761/ICST.100022828706734
     [Google Scholar]
  29. WangR. ZhuY. LiuX. LiaoX. HeJ. NiuL. The Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer.BMC Cancer2019191109110.1186/s12885‑019‑6311‑z31718602
     [Google Scholar]
  30. AsadiM.R. RahmanpourD. MoslehianM.S. Stress granules involved in formation, progression and metastasis of cancer: A scoping review.Front. Cell Dev. Biol.2021974539410.3389/fcell.2021.74539434604242
     [Google Scholar]
  31. ChenJ.F. YanQ. The roles of epigenetics in cancer progression and metastasis.Biochem. J.2021478173373339310.1042/BCJ2021008434520519
     [Google Scholar]
  32. MingH. LiB. ZhouL. GoelA. HuangC. Long non-coding RNAs and cancer metastasis: Molecular basis and therapeutic implications.Biochim. Biophys. Acta Rev. Cancer20211875218851910.1016/j.bbcan.2021.18851933548345
     [Google Scholar]
  33. Filippov-LevyN. ReichR. DavidsonB. The Biological and Clinical Role of the Long Non-Coding RNA LOC642852 in Ovarian Carcinoma.Int. J. Mol. Sci.20202115523710.3390/ijms2115523732718068
     [Google Scholar]
  34. DesgrosellierJ.S. ChereshD.A. Integrins in cancer: biological implications and therapeutic opportunities.Nat. Rev. Cancer201010192210.1038/nrc274820029421
     [Google Scholar]
  35. HoweG.A. AddisonC.L. β1 integrin.Cell Adhes. Migr.201262717710.4161/cam.2007722568952
     [Google Scholar]
  36. PanB. GuoJ. LiaoQ. ZhaoY. β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication.(Review)Oncol. Lett.20181545412541610.3892/ol.2018.807629556293
     [Google Scholar]
  37. TruongH.H. XiongJ. GhotraV.P.S. β1 integrin inhibition elicits a prometastatic switch through the TGFβ-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer.Sci. Signal.20147312ra1510.1126/scisignal.200475124518294
     [Google Scholar]
  38. LiuH. RadiskyD.C. YangD. MYC suppresses cancer metastasis by direct transcriptional silencing of αv and β3 integrin subunits.Nat. Cell Biol.201214656757410.1038/ncb249122581054
     [Google Scholar]
  39. MiskinR.P. WarrenJ.S.A. NdoyeA. WuL. LamarJ.M. DiPersioC.M. Integrin α3β1 promotes invasive and metastatic properties of breast cancer cells through induction of the Brn-2 transcription factor.Cancers (Basel)202113348010.3390/cancers1303048033513758
     [Google Scholar]
  40. YeungK.T. YangJ. Epithelial–mesenchymal transition in tumor metastasis.Mol. Oncol.2017111283910.1002/1878‑0261.1201728085222
     [Google Scholar]
  41. TrimboliA.J. FukinoK. de BruinA. Direct evidence for epithelial-mesenchymal transitions in breast cancer.Cancer Res.200868393794510.1158/0008‑5472.CAN‑07‑214818245497
     [Google Scholar]
  42. PadmanabanV. KrolI. SuhailY. E-cadherin is required for metastasis in multiple models of breast cancer.Nature2019573777443944410.1038/s41586‑019‑1526‑331485072
     [Google Scholar]
  43. BussardK.M. MutkusL. StumpfK. Gomez-ManzanoC. MariniF.C. Tumor-associated stromal cells as key contributors to the tumor microenvironment.Breast Cancer Res.20161818410.1186/s13058‑016‑0740‑227515302
     [Google Scholar]
  44. QianB.Z. ZhangH. LiJ. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis.J. Exp. Med.201521291433144810.1084/jem.2014155526261265
     [Google Scholar]
  45. PlantamuraI. CasaliniP. DugnaniE. PDGFRβ and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells.Mol. Oncol.20148596898110.1016/j.molonc.2014.03.01524747080
     [Google Scholar]
  46. D’IppolitoE. PlantamuraI. BongiovanniL. miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer.Cancer Res.201676185562557210.1158/0008‑5472.CAN‑16‑014027402080
     [Google Scholar]
  47. JenaM.K. JanjanamJ. Role of extracellular matrix in breast cancer development: a brief update.F1000 Res.2018727410.12688/f1000research.14133.229983921
     [Google Scholar]
  48. MajmundarA.J. WongW.J. SimonM.C. Hypoxia-inducible factors and the response to hypoxic stress.Mol. Cell201040229430910.1016/j.molcel.2010.09.02220965423
     [Google Scholar]
  49. KrockB.L. SkuliN. SimonM.C. Hypoxia-induced angiogenesis: good and evil.Genes Cancer20112121117113310.1177/194760191142365422866203
     [Google Scholar]
  50. RankinE.B. GiacciaA.J. Hypoxic control of metastasis.Science2016352628217518010.1126/science.aaf440527124451
     [Google Scholar]
  51. LiuZ. SemenzaG.L. ZhangH. Hypoxia-inducible factor 1 and breast cancer metastasis.J. Zhejiang Univ. Sci. B2015161324310.1631/jzus.B140022125559953
     [Google Scholar]
  52. BosR. van der GroepP. GreijerA.E. Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma.Cancer20039761573158110.1002/cncr.1124612627523
     [Google Scholar]
  53. GruberG. GreinerR.H. HlushchukR. Hypoxia-inducible factor 1 alpha in high-risk breast cancer: An independent prognostic parameter?Breast Cancer Res.200463R191R19810.1186/bcr77515084243
     [Google Scholar]
  54. GeneraliD. BerrutiA. BrizziM.P. Hypoxia-inducible factor-1α expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer.Clin. Cancer Res.200612154562456810.1158/1078‑0432.CCR‑05‑269016899602
     [Google Scholar]
  55. ZhangH. WongC.C.L. WeiH. RETRACTED ARTICLE: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs.Oncogene201231141757177010.1038/onc.2011.36521860410
     [Google Scholar]
  56. DastmalchiN. HosseinpourfeiziM.A. KhojastehS.M.B. BaradaranB. SafaralizadehR. Tumor suppressive activity of miR-424-5p in breast cancer cells through targeting PD-L1 and modulating PTEN/PI3K/AKT/mTOR signaling pathway.Life Sci.202025911823910.1016/j.lfs.2020.11823932784058
     [Google Scholar]
  57. XuanJ. LiuY. ZengX. WangH. Sequence requirements for miR-424-5p regulating and function in cancers.Int. J. Mol. Sci.2022237403710.3390/ijms2307403735409396
     [Google Scholar]
  58. KalantzakosT.J. SullivanT.B. GloriaT. CanesD. MoinzadehA. Rieger-ChristK.M. MiRNA-424-5p suppresses proliferation, migration, and invasion of clear cell renal cell carcinoma and attenuates expression of O-GlcNAc-transferase.Cancers (Basel)20211320516010.3390/cancers1320516034680309
     [Google Scholar]
  59. WangJ WangS ZhouJ QianQ. miR-424-5p regulates cell proliferation, migration and invasion by targeting doublecortin-like kinase 1 in basal-like breast cancer.Biomed pharmacoth 201810214752
     [Google Scholar]
  60. DastmalchiN. SafaralizadehR. HosseinpourfeiziM.A. BaradaranB. KhojastehS.M.B. MicroRNA-424-5p enhances chemosensitivity of breast cancer cells to Taxol and regulates cell cycle, apoptosis, and proliferation.Mol. Biol. Rep.20214821345135710.1007/s11033‑021‑06193‑433555529
     [Google Scholar]
  61. ZouT. GaoY. QieM. MiR-29c-3p inhibits epithelial-mesenchymal transition to inhibit the proliferation, invasion and metastasis of cervical cancer cells by targeting SPARC.Ann. Transl. Med.20219212510.21037/atm‑20‑727233569427
     [Google Scholar]
  62. LouW. DingB. ZhongG. YaoJ. FanW. FuP. RP11-480I12.5-004 promotes growth and tumorigenesis of breast cancer by relieving miR-29c-3p-mediated AKT3 and CDK6 degradation.Mol. Ther. Nucleic Acids20202191693110.1016/j.omtn.2020.07.02232810693
     [Google Scholar]
  63. LvT. JiangL. KongL. YangJ. MicroRNA 29c 3p acts as a tumor suppressor gene and inhibits tumor progression in hepatocellular carcinoma by targeting TRIM31.Oncol. Rep.202043395396410.3892/or.2020.746932020206
     [Google Scholar]
  64. ZhangQ. ZhuH. XiaM. A panel of collagen genes are associated with prognosis of patients with gastric cancer and regulated by microRNA-29c-3p: An integrated bioinformatics analysis and experimental validation.Cancer Manag. Res.2019114757477210.2147/CMAR.S19833131213898
     [Google Scholar]
  65. GrassilliS. BertagnoloV. BrugnoliF. Mir-29b in breast cancer: A promising target for therapeutic approaches.Diagnostics 2022129213910.3390/diagnostics1209213936140539
     [Google Scholar]
  66. SantarosaM. BaldazziD. ArmellinM. MaestroR. In silico identification of a BRCA1:miR-29:DNMT3 axis involved in the control of hormone receptors in brca1-associated breast cancers.Int. J. Mol. Sci.20232412991610.3390/ijms2412991637373065
     [Google Scholar]
  67. GustincichS. VattaP. GoruppiS. The human serum deprivation response gene (SDPR) maps to 2q32-q33 and codes for a phosphatidylserine-binding protein.Genomics199957112012910.1006/geno.1998.573310191091
     [Google Scholar]
  68. FriedrichK. WeberT. ScheithauerJ. Chromosomal genotype in breast cancer progression: comparison of primary and secondary manifestations.Cell. Oncol.20083013950[PMID: 18219109
     [Google Scholar]
  69. OzturkS. PapageorgisP. WongC.K. SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis.Proc. Natl. Acad. Sci. USA2016113363864310.1073/pnas.151466311326739564
     [Google Scholar]
  70. PignatelliJ. TumbarelloD.A. SchmidtR.P. TurnerC.E. Hic-5 promotes invadopodia formation and invasion during TGF-β–induced epithelial–mesenchymal transition.J. Cell Biol.2012197342143710.1083/jcb.20110814322529104
     [Google Scholar]
  71. AnneckeK. SchmittM. EulerU. uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial.Adv. Clin. Chem.20084545314510.1016/S0065‑2423(07)00002‑918429492
     [Google Scholar]
  72. HuQ. LuY-Y. NohH. Interleukin enhancer-binding factor 3 promotes breast tumor progression by regulating sustained urokinase-type plasminogen activator expression.Oncogene201332343933394310.1038/onc.2012.41422986534
     [Google Scholar]
  73. MazumdarM. SundareshanS. MisteliT. Human chromokinesin KIF4A functions in chromosome condensation and segregation.J. Cell Biol.2004166561362010.1083/jcb.20040114215326200
     [Google Scholar]
  74. HuC.K. CoughlinM. FieldC.M. MitchisonT.J. KIF4 regulates midzone length during cytokinesis.Curr. Biol.2011211081582410.1016/j.cub.2011.04.01921565503
     [Google Scholar]
  75. XueD. ChengP. HanM. An integrated bioinformatical analysis to evaluate the role of KIF4A as a prognostic biomarker for breast cancer.OncoTargets Ther.2018114755476810.2147/OTT.S16473030127624
     [Google Scholar]
  76. HildebrandK.A. FrankC.B. HartD.A. Gene intervention in ligament and tendon: current status, challenges, future directions.Gene Ther.200411436837810.1038/sj.gt.330219814724683
     [Google Scholar]
  77. BirkD.E. FitchJ.M. BabiarzJ.P. DoaneK.J. LinsenmayerT.F. Collagen fibrillogenesis in vitro: Interaction of types I and V collagen regulates fibril diameter.J. Cell Sci.199095464965710.1242/jcs.95.4.6492384532
     [Google Scholar]
  78. ZhaoB. SongX. GuanH. CircACAP2 promotes breast cancer proliferation and metastasis by targeting miR-29a/b-3p-COL5A1 axis.Life Sci.202024411717910.1016/j.lfs.2019.11717931863774
     [Google Scholar]
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Key LncRNAs Associated with Distant Metastasis in Breast Cancer: A System Biology Analysis
MicroRNA 14, 124 (2025); https://doi.org/10.2174/0122115366319044241015065537
/content/journals/mirna/10.2174/0122115366319044241015065537
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  • Article Type:     Research Article
Keyword(s): bioinformatics; Breast cancer; hub gene; lncRNA; metastasis; WGCNA

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