# An Emerging Role of Long Noncoding RNAs as Novel Biomarkers for Breast Cancer Metastasis
## 3 Molecular and Functional Insights into Breast Cancer Metastasis
### Role of lncRNAs Involved in Breast Cancer Metastasis Processes  
In the complex process of BC metastasis, the pivotal roles of lncRNAs are highlighted, especially in the dissemination of cancer cells to regional lymph nodes (LNs), which significantly influences disease progression and patient outcomes. At the transcriptional level, lncRNAs serve as decoys, guides, scaffold molecules, and enhancers to modulate gene expression. For instance, Hox Transcript Antisense Intergenic (HOTAIR) acts as a scaffold for Polycomb Repressive Complex 2 (PRC2), facilitating the epigenetic silencing of metastasis-suppressor genes such as E-cadherin. Additionally, guiding lncRNAs like KCNQ1 OT1 interact with transcriptional co-regulators to modulate gene transcription. Moreover, scaffolding lncRNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and enhancing lncRNA-SLC4A1-140 participate in forming ribonucleoprotein complexes and stabilizing enhancer-promoter interactions, respectively, further influencing gene expression profiles associated with metastasis [15]. At the post-transcriptional level, lncRNAs regulate mRNA stability, mRNA splicing, protein translation, and protein stability. For example, MALAT1 modulates alternative splicing patterns by interacting with splicing  
Figure 1: Classification of lncRNAs based on genomic location. (**A**) Transcribed from the same DNA strand as neighboring protein-coding genes. (**B**) Transcribed from the opposite strand, affecting mRNA stability, splicing, or translation. (**C**) Located within protein-coding gene introns, regulating host or nearby genes through splicing and serving as precursors for small RNAs. (**D**) Found between genes, acting as epigenetic regulators by modifying chromatin states and interacting with chromatin complexes. (**E**) Transcribed near a gene’s promoter in the opposite direction, regulating nearby genes by affecting transcription initiation or chromatin structure. (**F**) Originating from enhancer regions, facilitating enhancer-promoter interactions, transcription, and transcription factor positioning. Image created with Canva Pro, [[https://www.canva.com/pro/](https://www.canva.com/pro/)]([https://www.canva.com/pro/](https://www.canva.com/pro/)) (accessed on 25 July 2024).  
factors, while growth arrest-specific 5 (GAS5) stabilizes mRNA molecules by forming RNA duplexes. Furthermore, lncRNA Regulator of Reprogramming (lncRNA-ROR) and lncRNA Interactive partner (lincIN) regulate protein translation, while anti-differentiation noncoding RNA (ANCR) and lncRNA Low Expression in Tumor (lncRNA-LET) contribute to protein stability by facilitating ubiquitination and degradation. Epigenetically, lncRNAs such as HOTAIR and linc-ROR regulate histone modifications and chromatin remodeling, while others like H19 and XIST control DNA methylation, thereby shaping the epigenetic landscape conducive to LNM [13]. The Epithelial-Mesenchymal Transition (EMT) is a pivotal process in BC metastasis, where epithelial cells acquire traits typical of mesenchymal cells, enhancing their ability to migrate and invade surrounding tissues. LncRNAs play a crucial role in regulating genes critical for the EMT by interacting with protein complexes, chromatin-modifying enzymes, and transcription factors. Moreover, they modulate signaling pathways such as Wnt, TGF-\(\beta\), or NF-\(\kappa\)B, which are pivotal for the EMT, thus impacting the metastatic spread of BC cells. Consequently, lncRNAs emerge as key regulators in driving or suppressing the EMT process, influencing the metastatic potential of BC [16].