Differential Expression of MALAT1 and HOTAIR lncRNAs in Early and Advanced Stage Breast Cancer Patients: Potential Prognostic Biomarkers

Trends in Immunotherapy

Article

Differential Expression of MALAT1 and HOTAIR lncRNAs in Early and Advanced Stage Breast Cancer Patients: Potential Prognostic Biomarkers

Ali, H., UM, T., Shrivastav, D., Mirza, M. A. B., Sharma, V. K., & Verma, A. (2026). Differential Expression of MALAT1 and HOTAIR lncRNAs in Early and Advanced Stage Breast Cancer Patients: Potential Prognostic Biomarkers. Trends in Immunotherapy, 10(1), 117–129. https://doi.org/10.54963/ti.v10i1.1521

Authors

  • Haider Ali

    Department of Basic and Clinical Pharmacology, Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Tilekeeva UM

    Department of Basic and Clinical Pharmacology, Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Dharmsheel Shrivastav

    Department of Biotechnology and Microbiology, Noida International University, Greater Noida 201003, India
  • Masroor Ali Beg Mirza

    Faculty of Medicine, Alatoo International University, Bishkek 720048, Kyrgyzstan
  • Varun Kumar Sharma

    Department of Biotechnology and Microbiology, Noida International University, Greater Noida 201003, India
  • Amit Verma

    Division of Diagnostic Innovation, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6129, USA

Received: 11 September 2025; Revised: 17 November 2025; Accepted: 25 November 2025; Published: 3 February 2026

Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression involved in tumor initiation, progression, and metastasis. Among them, HOTAIR (HOX Transcript Antisense Intergenic RNA) and MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) have been implicated in several cancers, including breast cancer. However, their stage-specific expression patterns and prognostic relevance in breast cancer remain underexplored. This study aimed to evaluate the differential expression of HOTAIR and MALAT1 in early-stage (I–II) and late-stage (III–IV) breast cancers and to assess their association with clinicopathological and demographic parameters to determine their potential as prognostic biomarkers. Eighty breast cancer samples were analyzed for HOTAIR and MALAT1 expression using qRT-PCR. Clinicopathological data, including age, menopausal status, lymph node involvement, and hormone receptor status (ER, PR, HER2/neu), were collected. Logistic regression, ROC curve, and univariate analyses assessed their diagnostic and predictive significance. HOTAIR expression was significantly upregulated in late-stage (III–IV) breast cancer compared with early-stage (I–II) cases (p < 0.05), showing strong association with lymph node metastasis, postmenopausal status, and receptor negativity. ROC analysis demonstrated HOTAIR’s predictive potential with an AUC of 0.73 (sensitivity: 64%; specificity: 86%). MALAT1 expression was non-significantly elevated in late-stage tumors. Logistic regression analysis we observed that overexpression of HOTAIR, lymph node involvement, and hormone receptor negativity as increases disease risk. The findings indicate that HOTAIR over expression serves as a potential prognostic biomarker for breast cancer at late stage and associated with clinicopathological features and disease progression.

Keywords:

Breast Cancer Long Non-Coding RNA MALAT1 HOTAIR Prognostic Markers

References

  1. Feng, Y.; Spezia, M.; Huang, S.; et al. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis. 2018, 5, 77–106.
  2. Anand, U.; Dey, A.; Chandel, A.K.; et al. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2022, 10, 1367–1401. DOI: https://doi.org/10.1016/j.gendis.2022.02.007
  3. Takeshima, H.; Ushijima, T. Accumulation of genetic and epigenetic alterations in normal cells and cancer risk. NPJ Precis. Oncol. 2019, 3, 7. DOI: https://doi.org/10.1038/s41698-019-0079-0
  4. Kung, J.T.; Colognori, D.; Lee, J.T. Long noncoding RNAs: past, present, and future. Genetics 2013, 193, 651–669. DOI: https://doi.org/10.1534/genetics.112.146704
  5. Raju, G.S.R.; Pavitra, E.; Bandaru, S.S.; et al. HOTAIR: a potential metastatic, drug-resistant and prognostic regulator of breast cancer. Mol. Cancer 2023, 22, 65. DOI: https://doi.org/10.1186/s12943-023-01765-3
  6. Wang, J.; Liu, X.; Li, P.; et al. Long noncoding RNA HOTAIR regulates the stemness of breast cancer cells via activation of the NF-κB signaling pathway. J. Biol. Chem. 2022, 298, 102630. DOI: https://doi.org/10.1016/j.jbc.2022.102630
  7. Wang, J.; Ye, C.; Xiong, H.; et al. Dysregulation of long non-coding RNA in breast cancer: an overview of mechanism and clinical implication. Oncotarget 2017, 8, 5508–5522. DOI: https://doi.org/10.18632/oncotarget.12537
  8. Chen, Q.; Zhu, C.; Jin, Y. The oncogenic and tumor suppressive functions of the long noncoding RNA MALAT1: An emerging controversy. Front. Genet. 2020, 11, 93. DOI: https://doi.org/10.3389/fgene.2020.00093
  9. Eastlack, S.C.; Dong, S.; Mo, Y.Y.; et al. Expression of long noncoding RNA MALAT1 correlates with increased levels of Nischarin and inhibits oncogenic cell functions in breast cancer. PLoS One 2018, 13, e0198945. DOI: https://doi.org/10.1371/journal.pone.0198945
  10. Hassanzarei, S.; Hashemi, M.; Sattarifard, H.; et al. Genetic polymorphisms of HOTAIR gene are associated with the risk of breast cancer in a sample of southeast Iranian population. Tumour Biol. 2017, 39, 1010428317727539. DOI: https://doi.org/10.1177/1010428317727539
  11. Gilkes, D.M.; Semenza, G.L.; Wirtz, D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat. Rev. Cancer 2014, 14, 430–439. DOI: https://doi.org/10.1038/nrc3726
  12. Tsyganov, M.M.; Ibragimova, M.K. MALAT1 long non-coding RNA and its role in breast carcinogenesis. Acta Naturae 2023, 15, 32–41. DOI: https://doi.org/10.32607/actanaturae.11905
  13. Anbiyaee, O.; Moalemnia, A.; Ghaedrahmati, F.; et al. The functions of long non-coding RNA (lncRNA)-MALAT-1 in the pathogenesis of renal cell carcinoma. BMC Nephrol. 2023, 24, 380. DOI: https://doi.org/10.1186/s12882-023-03438-1
  14. Shih, C.H.; Chuang, L.L.; Tsai, M.H.; et al. Hypoxia-induced MALAT1 promotes the proliferation and migration of breast cancer cells by sponging MiR-3064-5p. Front. Oncol. 2021, 11, 658151. DOI: https://doi.org/10.3389/fonc.2021.658151
  15. Pilleron, S.; Soto-Perez-de-Celis, E.; Vignat, J.; et al. Estimated global cancer incidence in the oldest adults in 2018 and projections to 2050. Int. J. Cancer 2021, 148, 601–608. DOI: https://doi.org/10.1002/ijc.33232
  16. White, M.C.; Holman, D.M.; Boehm, J.E.; et al. Age and cancer risk: A potentially modifiable relationship. Am. J. Prev. Med. 2014, 46, S7–S15. DOI: https://doi.org/10.1016/j.amepre.2013.10.029
  17. Wang, R.; Wang, Y.; Fang, L.; et al. Efficacy and safety of traditional Chinese medicine in the treatment of menopause-like syndrome for breast cancer survivors: A systematic review and meta-analysis. BMC Cancer 2024, 24, 42. DOI: https://doi.org/10.1186/s12885-023-11789-z
  18. John, E.M.; Koo, J.; Phipps, A.I.; et al. Reproductive characteristics, menopausal status, race and ethnicity, and risk of breast cancer subtypes defined by ER, PR and HER2 status: The Breast Cancer Etiology in Minorities study. Breast Cancer Res. 2024, 26, 88. DOI: https://doi.org/10.1186/s13058-024-01834-5
  19. You, J.; Huang, Y.; Ouyang, L.; et al. Automated and reusable deep learning (AutoRDL) framework for predicting response to neoadjuvant chemotherapy and axillary lymph node metastasis in breast cancer using ultrasound images: A retrospective, multicentre study. EClinicalMedicine 2024, 69, 102499. DOI: https://doi.org/10.1016/j.eclinm.2024.102499
  20. Yang, Z.; Ji, Y.; Jia, Q.; et al. Real-time detection and resection of sentinel lymph node metastasis in breast cancer through a rare earth nanoprobe based NIR-IIb fluorescence imaging. Mater. Today Bio 2024, 28, 101166. DOI: https://doi.org/10.1016/j.mtbio.2024.101166
  21. Bitaraf, A.; Zafarani, A.; Jahandideh, P.; et al. MALAT1 as a molecular driver of tumor progression, immune evasion, and resistance to therapy. Mol. Cancer 2025, 24, 245. DOI: https://doi.org/10.1186/s12943-025-02415-6
  22. Arshi, A.; Raeisi, F.; Mahmoudi, E.; et al. A Comparative Study of HOTAIR Expression in Breast Cancer Patient Tissues and Cell Lines. Cell J. 2020, 22, 178–184. DOI: https://doi.org/10.22074/cellj.2020.6543
  23. Qian, L.; Li, L.; Li, Y.; et al. LncRNA HOTAIR as a ceRNA is related to breast cancer risk and prognosis. Breast Cancer Res. Treat. 2023, 200, 375–390. DOI: https://doi.org/10.1007/s10549-023-06982-4
  24. Abba, M.C.; Fabre, M.L.; Lee, J.; et al. HOTAIR Modulated Pathways in Early-Stage Breast Cancer Progression. Front. Oncol. 2021, 11, 783211.
  25. Zhang, S.; Wang, B.; Xiao, H.; et al. LncRNA HOTAIR enhances breast cancer radioresistance through facilitating HSPA1A expression via sequestering miR-449b-5p. Thorac. Cancer 2020, 11, 1801–1816.
  26. Wang, Z.; Katsaros, D.; Biglia, N.; et al. High expression of long non-coding RNA MALAT1 in breast cancer is associated with poor relapse-free survival. Breast Cancer Res. Treat. 2018, 171, 261–271. DOI: https://doi.org/10.1007/s10549-018-4839-2
  27. Serrano García, L.; Jávega, B.; Llombart Cussac, A.; et al. Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review. Front. Immunol. 2024, 15, 1513421. DOI: https://doi.org/10.3389/fimmu.2024.1513421
  28. Arun, G.; Spector, D.L. MALAT1 long non-coding RNA and breast cancer. RNA Biol. 2019, 16, 860–863. DOI: https://doi.org/10.1080/15476286.2019.1592072
  29. Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012, 13, 1141–1151. DOI: https://doi.org/10.1016/S1470-2045(12)70425-4
  30. Solak, M.; Turkoz, F.P.; Keskin, O.; et al. The lymph node ratio as an independent prognostic factor for non-metastatic node-positive breast cancer recurrence and mortality. J. BUON 2015, 20, 737–745.
  31. Shi, X.S.; Li, J.; Yang, R.H.; et al. Correlation of increased MALAT1 expression with pathological features and prognosis in cancer patients: A meta-analysis. Genet Mol Res. 2015, 14, 18808–18819.
  32. Saltzman, B.S.; Malone, K.E.; McDougall, J.A.; et al. Estrogen receptor, progesterone receptor, and HER2-neu expression in first primary breast cancers and risk of second primary contralateral breast cancer. Breast Cancer Res. Treat. 2012, 135, 849–855. DOI: https://doi.org/10.1007/s10549-012-2183-5
  33. Arnedos, M.; Bihan, C.; Delaloge, S.; et al. Triple-negative breast cancer: are we making headway at least?. Ther. Adv. Med. Oncol. 2012, 4, 195–210. DOI: https://doi.org/10.1177/1758834012444711
  34. Martin, C.J.; Moorehead, R.A. Polycomb repressor complex 2 function in breast cancer (Review). Int. J. Oncol. 2020, 57, 1085–1094. DOI: https://doi.org/10.3892/ijo.2020.5122
  35. Tripathi, V.; Shen, Z.; Chakraborty, A.; et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet. 2013, 9, e1003368. DOI: https://doi.org/10.1371/journal.pgen.1003368
  36. Wu, T.; Dong, Y.; Yang, X.; et al. Crosstalk between lncRNAs and Wnt/β-catenin signaling pathways in lung cancers: From cancer progression to therapeutic response. Non-coding RNA Res. 2024, 9, 667–677. DOI: https://doi.org/10.1016/j.ncrna.2024.02.013
  37. Shi, Y.; Huang, Q.; Kong, X.; et al. Current Knowledge of Long Non-Coding RNA HOTAIR in Breast Cancer Progression and Its Application. Life 2021, 11, 483. DOI: https://doi.org/10.3390/life11060483
  38. Xiping, Z.; Bo, C.; Shifeng, Y.; et al. Roles of MALAT1 in development and migration of triple-negative and Her-2 positive breast cancer. Oncotarget 2017, 9, 2255–2267. DOI: https://doi.org/10.18632/oncotarget.23370
  39. Li, Z.X.; Zhu, Q.N.; Zhang, H.B.; et al. MALAT1: a potential biomarker in cancer. Cancer Manag. Res. 2018, 10, 6757–6768. DOI: https://doi.org/10.2147/CMAR.S169406
  40. Sharma, V.K.; Raimondi, V.; Ruggero, K.; et al. Expression of miR-34a in T-Cells Infected by Human T-Lymphotropic Virus 1. Front. Microbiol. 2018, 9, 832. DOI: https://doi.org/10.3389/fmicb.2018.00832
  41. Ruggero, K.; Guffanti, A.; Corradin, A.; et al. Small noncoding RNAs in cells transformed by human T-cell leukemia virus type 1: a role for a tRNA fragment as a primer for reverse transcriptase. J. Virol. 2014, 88, 3612–3622. DOI: https://doi.org/10.1128/JVI.02823-13
  42. Xiong, X.; Zheng, L.W.; Ding, Y.; et al. Breast cancer: pathogenesis and treatments. Signal Transduct. Target. Ther. 2025, 10, 49. DOI: https://doi.org/10.1038/s41392-024-02108-4
  43. Orsaria, M.; Mangogna, A.; Bertoli, M.; et al. Breast Lesions of Uncertain Malignant Potential and Risk of Breast Cancer Development: A Single-Center Experience on 10,531 Consecutive Biopsies. Medicina 2025, 61, 1877. DOI: https://doi.org/10.3390/medicina61101877
  44. Li, Y.; Liu, F.; Cai, Q.; et al. Invasion and metastasis in cancer: molecular insights and therapeutic targets. Signal Transduct. Target. Ther. 2025, 10, 57. DOI: https://doi.org/10.1038/s41392-025-02148-4
  45. Yang, H.; Fang, Y.; Wang, H.; et al. Progress in epigenetic research of breast cancer: a bibliometric analysis since the 2000s. Front. Oncol. 2025, 15, 1619346. DOI: https://doi.org/10.3389/fonc.2025.1619346
  46. Xu, S.; Wang, L.; Zhao, Y.; et al. Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications. J. Biomed. Sci. 2024, 31, 25. DOI: https://doi.org/10.1186/s12929-024-01013-w
  47. Abdel-Hamid, N.R.; Mohammed, E.A.; Toraih, E.A.; et al. Circulating ESR1, long non-coding RNA HOTAIR and microRNA-130a gene expression as biomarkers for breast cancer stage and metastasis. Sci. Rep. 2023, 13, 22654. DOI: https://doi.org/10.1038/s41598-023-50007-5