# An Emerging Role of Long Noncoding RNAs as Novel Biomarkers for Breast Cancer Metastasis
## 5 Potential lncRNA-Based Biomarkers
### Hotair  
HOTAIR is a 2.158-nucleotide-long lncRNA expressed from the HOXC locus on chromosome 12q13.13. The role of HOTAIR in normal development is multifaceted, encompassing its involvement in gene regulation, scaffold formation, and cell cycle progression. Numerous studies have confirmed a strong association between HOTAIR expression and metastasis. They revealed an overexpression of HOTAIR within BC cells and tumor tissues, closely linked to both cell proliferation and the dissemination of cancer cells. HOTAIR emerged as a pioneering lncRNA identified to facilitate tumor progression and linked with unfavorable outcomes in BC cases [31]. [PERSON] et al. demonstrated that HOTAIR expression showed a bimodal distribution in primary BC, with metastatic BC patients displaying higher levels of HOTAIR. Additionally, individuals with elevated HOTAIR level had worse survival outcomes compared to those with low expression, particularly among ER-positive patients. These findings suggested that HOTAIR expression might serve as an independent biomarker for predicting metastasis risk in ER-positive BC patients but not in ER-negative BC [6]. On the contrary, a study by [PERSON] et al. demonstrated that elevated HOTAIR expression correlated with metastatic progression, particularly in ER-negative BC. However, its prognostic relevance appeared restricted to ER-negative, LN-positive tumors. The observed differences might stem from variations in cohort sizes, the ratio of ER-positive to ER-negative patients, and the endpoints selected for both analyses [32]. [PERSON] et al. assessed the in situ expression of HOTAIR in numerous case series of patients with TNBC by employing ISH techniques with an RNA probe. It revealed a strong correlation between elevated HOTAIR levels and the metastasis of tumor cells to the LNs. Furthermore, they identified a  
Figure 2: (1) Expression of potential lncRNA-based biomarkers for breast cancer and (2) their association with distant metastasis. 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). direct association between HOTAIR expression and androgen receptor (AR) expression, suggesting a potential role of HOTAIR in regulating the AR pathway in TNBC [14]. The potential of HOTAIR as an indicator of BC metastasis was also confirmed by the study conducted by [PERSON] et al., wherein its expression was significantly elevated both in peripheral blood mononuclear and cancerous tissue samples from patients with BC migration to the LNs. The results also suggested that G protein-Coupled Estrogen Receptor (GPER) regulates E2-induced HOTAIR levels in BC cells, and E2/GPER enhances these levels through miR-148a. Hence, in ER-negative BC, E2-ER increases HOTAIR by binding to ERE in its promoter, while in TNBC, E2-GPER boosts HOTAIR by inhibiting miR-148a, which recognizes the sequence within HOTAIR [33]. [PERSON] et.al found that HOTAIR expression in plasma significantly correlated with ER level and LNM. Following surgery, patients exhibited a marked decrease in HOTAIR levels, which moderately correlated with its expression in tumor tissues. Notably, plasma HOTAIR demonstrated superior diagnostic sensitivity and specificity compared to Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 153 (CA153); meanwhile, combining these three markers allowed for increased diagnostic power [34]. The integration of various studies highlights HOTAIR's significant role in promoting BC progression through multiple pathways, particularly EMT regulation, critical for metastasis to LNs and other organs. Elevated levels of HOTAIR triggered by TGF-\(\beta\)1 stimulate the EMT, whereas its suppression through siRNA prevents this transition and reduces the colony-forming ability of colon and BC cells [9]. The activity of various miRNAs, particularly in BC, significantly influences the modulation of the EMT process and subsequent metastasis induction in BC.