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Cellular and Molecular Biology

Expression and functions of long non-coding RNA NEAT1 and isoforms in breast cancer

British Journal of Cancer volume 126, pages 551–561 (2022)Cite this article

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Abstract

NEAT1 is a highly abundant nuclear architectural long non-coding RNA. There are two overlapping NEAT1 isoforms, NEAT1_1 and NEAT1_2, of which the latter is an essential scaffold for the assembly of a class of nuclear ribonucleoprotein bodies called paraspeckles. Paraspeckle formation is elevated by a wide variety of cellular stressors and in certain developmental processes, either through transcriptional upregulation of the NEAT1 gene or through a switch from NEAT1_1 to NEAT1_2 isoform production. In such conditions, paraspeckles modulate cellular processes by sequestering proteins or RNA molecules. NEAT1 is abnormally expressed in many cancers and a growing body of evidence suggests that, in many cases, high NEAT1 levels are associated with therapy resistance and poor clinical outcome. Here we review the current knowledge of NEAT1 expression and functions in breast cancer, highlighting its established role in postnatal mammary gland development. We will discuss possible isoform-specific roles of NEAT1_1 and NEAT1_2 in different breast cancer subtypes, which critically needs to be considered when studying NEAT1 and breast cancer.

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Fig. 1: Two isoforms of NEAT1 with distinct functions arise from alternative transcriptional termination and processing.
Fig. 2: Paraspeckles regulate cellular processes by molecular sequestration.
Fig. 3: NEAT1_2 and paraspeckle formation are upregulated by malignancy-associated stress and confer therapy resistance.
Fig. 4: Distinct NEAT1 isoform distribution in breast cancer subtypes.

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References

  1. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021;22:96–118.

    Article  CAS  PubMed  Google Scholar 

  2. Yao RW, Wang Y, Chen LL. Cellular functions of long noncoding RNAs. Nat Cell Biol. 2019;21:542–51.

    Article  CAS  PubMed  Google Scholar 

  3. Zhao Y, Teng H, Yao F, Yap S, Sun Y, Ma L. Challenges and strategies in ascribing functions to long noncoding RNAs. Cancers. 2020;12:1458.

  4. Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172:393–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fox AH, Nakagawa S, Hirose T, Bond CS. Paraspeckles: where long noncoding RNA meets phase separation. Trends Biochem Sci. 2018;43:124–35.

    Article  CAS  PubMed  Google Scholar 

  6. Hirose T, Yamazaki T, Nakagawa S. Molecular anatomy of the architectural NEAT1 noncoding RNA: the domains, interactors, and biogenesis pathway required to build phase-separated nuclear paraspeckles. Wiley Interdiscip Rev RNA. 2019;10:e1545.

    Article  PubMed  Google Scholar 

  7. Nakagawa S, Yamazaki T, Hirose T. Molecular dissection of nuclear paraspeckles: towards understanding the emerging world of the RNP milieu. Open Biol. 2018;8:180150.

  8. Yang C, Li Z, Li Y, Xu R, Wang Y, Tian Y, et al. Long non-coding RNA NEAT1 overexpression is associated with poor prognosis in cancer patients: a systematic review and meta-analysis. Oncotarget. 2017;8:2672–80.

    Article  PubMed  Google Scholar 

  9. Fang J, Qiao F, Tu J, Xu J, Ding F, Liu Y, et al. High expression of long non-coding RNA NEAT1 indicates poor prognosis of human cancer. Oncotarget. 2017;8:45918–27.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Klec C, Prinz F, Pichler M. Involvement of the long noncoding RNA NEAT1 in carcinogenesis. Mol Oncol. 2019;13:46–60.

    Article  CAS  PubMed  Google Scholar 

  11. An H, Williams NG, Shelkovnikova TA. NEAT1 and paraspeckles in neurodegenerative diseases: a missing lnc found? Noncoding RNA Res. 2018;3:243–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hutchinson JN, Ensminger AW, Clemson CM, Lynch CR, Lawrence JB, Chess A. A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics. 2007;8:39.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lin Y, Schmidt BF, Bruchez MP, McManus CJ. Structural analyses of NEAT1 lncRNAs suggest long-range RNA interactions that may contribute to paraspeckle architecture. Nucleic Acids Res. 2018;46:3742–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guru SC, Agarwal SK, Manickam P, Olufemi SE, Crabtree JS, Weisemann JM, et al. A transcript map for the 2.8-Mb region containing the multiple endocrine neoplasia type 1 locus. Genome Res. 1997;7:725–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sunwoo H, Dinger ME, Wilusz JE, Amaral PP, Mattick JS, Spector DL. MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 2009;19:347–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sasaki YT, Ideue T, Sano M, Mituyama T, Hirose T. MENepsilon/beta noncoding RNAs are essential for structural integrity of nuclear paraspeckles. Proc Natl Acad Sci USA. 2009;106:2525–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Naganuma T, Nakagawa S, Tanigawa A, Sasaki YF, Goshima N, Hirose T. Alternative 3’-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J. 2012;31:4020–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Barra J, Gaidosh GS, Blumenthal E, Beckedorff F, Tayari MM, Kirstein N, et al. Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1. Sci Adv. 2020;6:eaaz9072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mendoza-Figueroa MS, Tatomer DC, Wilusz JE. The integrator complex in transcription and development. Trends Biochem Sci. 2020;45:923–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rienzo M, Casamassimi A. Integrator complex and transcription regulation: Recent findings and pathophysiology. Biochim Biophys Acta. 2016;1859:1269–80.

    Article  CAS  PubMed  Google Scholar 

  21. Modic M, Grosch M, Rot G, Schirge S, Lepko T, Yamazaki T, et al. Cross-regulation between TDP-43 and paraspeckles promotes pluripotency-differentiation transition. Mol Cell. 2019;74:951–65 e913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brown JA, Valenstein ML, Yario TA, Tycowski KT, Steitz JA. Formation of triple-helical structures by the 3’-end sequences of MALAT1 and MENbeta noncoding RNAs. Proc Natl Acad Sci USA. 2012;109:19202–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wilusz JE, JnBaptiste CK, Lu LY, Kuhn CD, Joshua-Tor L, Sharp PA. A triple helix stabilizes the 3’ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev. 2012;26:2392–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clemson CM, Hutchinson JN, Sara SA, Ensminger AW, Fox AH, Chess A, et al. An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol Cell. 2009;33:717–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yamazaki T, Souquere S, Chujo T, Kobelke S, Chong YS, Fox AH, et al. Functional domains of NEAT1 architectural lncRNA induce paraspeckle assembly through phase separation. Mol Cell. 2018;70:1038.e7–53.e7.

    Article  Google Scholar 

  26. Hennig S, Kong G, Mannen T, Sadowska A, Kobelke S, Blythe A, et al. Prion-like domains in RNA binding proteins are essential for building subnuclear paraspeckles. J Cell Biol. 2015;210:529–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang LZ, Wang Y, Li SQ, Yao RW, Luan PF, Wu H, et al. Dynamic imaging of RNA in living cells by CRISPR-Cas13 systems. Mol Cell. 2019;76:981.e7–97.e7.

    Article  Google Scholar 

  28. Chen LL, Carmichael GG. Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol Cell. 2009;35:467–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fox AH, Lam YW, Leung AK, Lyon CE, Andersen J, Mann M, et al. Paraspeckles: a novel nuclear domain. Curr Biol. 2002;12:13–25.

    Article  CAS  PubMed  Google Scholar 

  30. Mao YS, Sunwoo H, Zhang B, Spector DL. Direct visualization of the co-transcriptional assembly of a nuclear body by noncoding RNAs. Nat Cell Biol. 2011;13:95–101.

    Article  CAS  PubMed  Google Scholar 

  31. Fox AH, Bond CS, Lamond AI. P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an RNA-dependent manner. Mol Biol Cell. 2005;16:5304–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. An H, Tan JT, Shelkovnikova TA. Stress granules regulate stress-induced paraspeckle assembly. J Cell Biol. 2019;218:4127–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. West JA, Mito M, Kurosaka S, Takumi T, Tanegashima C, Chujo T, et al. Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization. J Cell Biol. 2016;214:817–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fong KW, Li Y, Wang W, Ma W, Li K, Qi RZ, et al. Whole-genome screening identifies proteins localized to distinct nuclear bodies. J Cell Biol. 2013;203:149–64.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yamazaki T, Hirose T. The building process of the functional paraspeckle with long non-coding RNAs. Front Biosci (Elite Ed). 2015;7:1–41.

    Article  Google Scholar 

  36. Knott GJ, Bond CS, Fox AH. The DBHS proteins SFPQ, NONO and PSPC1: a multipurpose molecular scaffold. Nucleic Acids Res. 2016;44:3989–4004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen B, Deng S, Ge T, Ye M, Yu J, Lin S, et al. Live cell imaging and proteomic profiling of endogenous NEAT1 lncRNA by CRISPR/Cas9-mediated knock-in. Protein Cell. 2020;11:641–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kawaguchi T, Tanigawa A, Naganuma T, Ohkawa Y, Souquere S, Pierron G, et al. SWI/SNF chromatin-remodeling complexes function in noncoding RNA-dependent assembly of nuclear bodies. Proc Natl Acad Sci USA. 2015;112:4304–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chujo T, Yamazaki T, Kawaguchi T, Kurosaka S, Takumi T, Nakagawa S, et al. Unusual semi-extractability as a hallmark of nuclear body-associated architectural noncoding RNAs. EMBO J. 2017;36:1447–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Franzmann TM, Alberti S. Prion-like low-complexity sequences: key regulators of protein solubility and phase behavior. J Biol Chem. 2019;294:7128–36.

    Article  CAS  PubMed  Google Scholar 

  41. Shelkovnikova TA, Robinson HK, Troakes C, Ninkina N, Buchman VL. Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Hum Mol Genet. 2014;23:2298–312.

    Article  CAS  PubMed  Google Scholar 

  42. Hirose T, Virnicchi G, Tanigawa A, Naganuma T, Li R, Kimura H, et al. NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. Mol Biol Cell. 2014;25:169–83.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wang Y, Hu SB, Wang MR, Yao RW, Wu D, Yang L, et al. Genome-wide screening of NEAT1 regulators reveals cross-regulation between paraspeckles and mitochondria. Nat Cell Biol. 2018;20:1145–58.

    Article  CAS  PubMed  Google Scholar 

  44. Shelkovnikova TA, Kukharsky MS, An H, Dimasi P, Alexeeva S, Shabir O, et al. Protective paraspeckle hyper-assembly downstream of TDP-43 loss of function in amyotrophic lateral sclerosis. Mol Neurodegener. 2018;13:30.

    Article  PubMed  PubMed Central  Google Scholar 

  45. McCluggage F, Fox AH. Paraspeckle nuclear condensates: global sensors of cell stress? Bioessays. 2021. https://doi.org/10.1002/bies.202000245.

  46. Li R, Harvey AR, Hodgetts SI, Fox AH. Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles. RNA. 2017;23:872–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Adriaens C, Rambow F, Bervoets G, Silla T, Mito M, Chiba T, et al. The long noncoding RNA NEAT1_1 is seemingly dispensable for normal tissue homeostasis and cancer cell growth. RNA. 2019;25:1681–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nakagawa S, Naganuma T, Shioi G, Hirose T. Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice. J Cell Biol. 2011;193:31–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Imamura K, Imamachi N, Akizuki G, Kumakura M, Kawaguchi A, Nagata K, et al. Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to paraspeckle mediates IL8 expression upon immune stimuli. Mol Cell. 2014;53:393–406.

    Article  CAS  PubMed  Google Scholar 

  50. Yarosh CA, Iacona JR, Lutz CS, Lynch KW. PSF: nuclear busy-body or nuclear facilitator? Wiley Interdiscip Rev RNA. 2015;6:351–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Torres M, Becquet D, Blanchard MP, Guillen S, Boyer B, Moreno M, et al. Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements. Elife. 2016;5:e14837.

  52. Prasanth KV, Prasanth SG, Xuan Z, Hearn S, Freier SM, Bennett CF, et al. Regulating gene expression through RNA nuclear retention. Cell. 2005;123:249–63.

    Article  CAS  PubMed  Google Scholar 

  53. Jiang L, Shao C, Wu QJ, Chen G, Zhou J, Yang B, et al. NEAT1 scaffolds RNA-binding proteins and the Microprocessor to globally enhance pri-miRNA processing. Nat Struct Mol Biol. 2017;24:816–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chakravarty D, Sboner A, Nair SS, Giannopoulou E, Li R, Hennig S, et al. The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat Commun. 2014;5:5383.

    Article  CAS  PubMed  Google Scholar 

  55. West JA, Davis CP, Sunwoo H, Simon MD, Sadreyev RI, Wang PI, et al. The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites. Mol Cell. 2014;55:791–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Grosch M, Ittermann S, Shaposhnikov D, Drukker M. Chromatin-associated membraneless organelles in regulation of cellular differentiation. Stem Cell Rep. 2020;15:1220–32.

    Article  CAS  Google Scholar 

  57. Lehnert SA, Reverter A, Byrne KA, Wang Y, Nattrass GS, Hudson NJ, et al. Gene expression studies of developing bovine longissimus muscle from two different beef cattle breeds. BMC Dev Biol. 2007;7:95.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Saha S, Murthy S, Rangarajan PN. Identification and characterization of a virus-inducible non-coding RNA in mouse brain. J Gen Virol. 2006;87:1991–5.

    Article  CAS  PubMed  Google Scholar 

  59. Beeharry Y, Goodrum G, Imperiale CJ, Pelchat M. The hepatitis delta virus accumulation requires paraspeckle components and affects NEAT1 level and PSP1 localization. Sci Rep. 2018;8:6031.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ma H, Han P, Ye W, Chen H, Zheng X, Cheng L, et al. The long noncoding RNA NEAT1 exerts antihantaviral effects by acting as positive feedback for RIG-I signaling. J Virol. 2017;91:e02250-16.

  61. Morchikh M, Cribier A, Raffel R, Amraoui S, Cau J, Severac D, et al. HEXIM1 and NEAT1 long non-coding RNA form a multi-subunit complex that regulates DNA-mediated innate immune response. Mol Cell. 2017;67:387.e5–99.e5.

    Article  Google Scholar 

  62. Wang Z, Fan P, Zhao Y, Zhang S, Lu J, Xie W, et al. NEAT1 modulates herpes simplex virus-1 replication by regulating viral gene transcription. Cell Mol Life Sci. 2017;74:1117–31.

    Article  CAS  PubMed  Google Scholar 

  63. Zhang Q, Chen CY, Yedavalli VS, Jeang KT. NEAT1 long noncoding RNA and paraspeckle bodies modulate HIV-1 posttranscriptional expression. MBio. 2013;4:e00596-00512.

    Article  Google Scholar 

  64. Choudhry H, Schodel J, Oikonomopoulos S, Camps C, Grampp S, Harris AL, et al. Extensive regulation of the non-coding transcriptome by hypoxia: role of HIF in releasing paused RNApol2. EMBO Rep. 2014;15:70–6.

    Article  CAS  PubMed  Google Scholar 

  65. Choudhry H, Albukhari A, Morotti M, Haider S, Moralli D, Smythies J, et al. Tumor hypoxia induces nuclear paraspeckle formation through HIF-2alpha dependent transcriptional activation of NEAT1 leading to cancer cell survival. Oncogene. 2015;34:4482–90.

    Article  CAS  PubMed  Google Scholar 

  66. Adriaens C, Standaert L, Barra J, Latil M, Verfaillie A, Kalev P, et al. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat Med. 2016;22:861–8.

    Article  CAS  PubMed  Google Scholar 

  67. Lellahi SM, Rosenlund IA, Hedberg A, Kiaer LT, Mikkola I, Knutsen E, et al. The long noncoding RNA NEAT1 and nuclear paraspeckles are up-regulated by the transcription factor HSF1 in the heat shock response. J Biol Chem. 2018;293:18965–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhou W, Chen X, Hu Q, Chen X, Chen Y, Huang L. Galectin-3 activates TLR4/NF-kappaB signaling to promote lung adenocarcinoma cell proliferation through activating lncRNA-NEAT1 expression. BMC Cancer. 2018;18:580.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Mello SS, Sinow C, Raj N, Mazur PK, Bieging-Rolett K, Broz DK, et al. Neat1 is a p53-inducible lincRNA essential for transformation suppression. Genes Dev. 2017;31:1095–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Blume CJ, Hotz-Wagenblatt A, Hullein J, Sellner L, Jethwa A, Stolz T, et al. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia. Leukemia. 2015;29:2015–23.

    Article  CAS  PubMed  Google Scholar 

  71. Wang Z, Li K, Huang W. Long non-coding RNA NEAT1-centric gene regulation. Cell Mol Life Sci. 2020;77:3769–79.

    Article  CAS  PubMed  Google Scholar 

  72. Nakagawa S, Shimada M, Yanaka K, Mito M, Arai T, Takahashi E, et al. The lncRNA Neat1 is required for corpus luteum formation and the establishment of pregnancy in a subpopulation of mice. Development. 2014;141:4618–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Standaert L, Adriaens C, Radaelli E, Van Keymeulen A, Blanpain C, Hirose T, et al. The long noncoding RNA Neat1 is required for mammary gland development and lactation. RNA. 2014;20:1844–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hupalowska A, Jedrusik A, Zhu M, Bedford MT, Glover DM, Zernicka-Goetz M. CARM1 and paraspeckles regulate pre-implantation mouse embryo development. Cell. 2018;175:1902.e13–16.e13.

    Article  Google Scholar 

  75. Gast M, Rauch BH, Haghikia A, Nakagawa S, Haas J, Stroux A, et al. Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients. Cardiovasc Res. 2019;115:1886–906.

    Article  CAS  PubMed  Google Scholar 

  76. Kukharsky MS, Ninkina NN, An H, Telezhkin V, Wei W, Meritens CR, et al. Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice. Transl Psychiatry. 2020;10:171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Katsel P, Roussos P, Fam P, Khan S, Tan W, Hirose T, et al. The expression of long noncoding RNA NEAT1 is reduced in schizophrenia and modulates oligodendrocytes transcription. NPJ Schizophr. 2019;5:3.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Ahmed ASI, Dong K, Liu J, Wen T, Yu L, Xu F, et al. Long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) is critical for phenotypic switching of vascular smooth muscle cells. Proc Natl Acad Sci USA. 2018;115:E8660–E8667.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ghafouri-Fard S, Taheri M. Nuclear enriched abundant transcript 1 (NEAT1): a long non-coding RNA with diverse functions in tumorigenesis. Biomed Pharmacother. 2019;111:51–59.

    Article  PubMed  Google Scholar 

  80. Dong P, Xiong Y, Yue J, Hanley SJB, Kobayashi N, Todo Y, et al. Long non-coding RNA NEAT1: a novel target for diagnosis and therapy in human tumors. Front Genet. 2018;9:471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yu X, Li Z, Zheng H, Chan MT, Wu WK. NEAT1: a novel cancer-related long non-coding RNA. Cell Prolif. 2017;50:e12329.

  82. Ronchetti D, Favasuli V, Monti P, Cutrona G, Fabris S, Silvestris I, et al. NEAT1 long isoform is highly expressed in chronic lymphocytic leukemia irrespectively of cytogenetic groups or clinical outcome. Noncoding RNA. 2020;6:11.

  83. Zeng C, Liu S, Lu S, Yu X, Lai J, Wu Y, et al. The c-Myc-regulated lncRNA NEAT1 and paraspeckles modulate imatinib-induced apoptosis in CML cells. Mol Cancer. 2018;17:130.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Zeng C, Xu Y, Xu L, Yu X, Cheng J, Yang L, et al. Inhibition of long non-coding RNA NEAT1 impairs myeloid differentiation in acute promyelocytic leukemia cells. BMC Cancer. 2014;14:693.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Duan MY, Li M, Tian H, Tang G, Yang YC, Peng NC. Down-regulation of lncRNA NEAT1 regulated by miR-194-5p/DNMT3A facilitates acute myeloid leukemia. Blood Cells Mol Dis. 2020;82:102417.

    Article  CAS  PubMed  Google Scholar 

  86. Feng S, Liu N, Chen X, Liu Y, An J. Long non-coding RNA NEAT1/miR-338-3p axis impedes the progression of acute myeloid leukemia via regulating CREBRF. Cancer Cell Int. 2020;20:112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rheinbay E, Nielsen MM, Abascal F, Wala JA, Shapira O, Tiao G, et al. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature. 2020;578:102–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rheinbay E, Parasuraman P, Grimsby J, Tiao G, Engreitz JM, Kim J, et al. Recurrent and functional regulatory mutations in breast cancer. Nature. 2017;547:55–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wedge DC, Gundem G, Mitchell T, Woodcock DJ, Martincorena I, Ghori M, et al. Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nat Genet. 2018;50:682–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Kato M, Shiraishi Y, et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet. 2016;48:500–9.

    Article  CAS  PubMed  Google Scholar 

  92. Huang J, Sachdeva M, Xu E, Robinson TJ, Luo L, Ma Y, et al. The long noncoding RNA NEAT1 promotes sarcoma metastasis by regulating RNA splicing pathways. Mol Cancer Res. 2020;18:1534–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Naveed A, Cooper JA, Li R, Hubbard A, Chen J, Liu T, et al. NEAT1 polyA-modulating antisense oligonucleotides reveal opposing functions for both long non-coding RNA isoforms in neuroblastoma. Cell Mol Life Sci. 2020. https://doi.org/10.1007/s00018-020-03632-6.

  94. Knutsen E, Lellahi SM, Aure MR, Nord S, Fismen S, Larsen KB, et al. The expression of the long NEAT1_2 isoform is associated with human epidermal growth factor receptor 2-positive breast cancers. Sci Rep. 2020;10:1277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Beca F, Polyak K. Intratumor heterogeneity in breast cancer. Adv Exp Med Biol. 2016;882:169–89.

    Article  CAS  PubMed  Google Scholar 

  96. Koren S, Bentires-Alj M. Breast tumor heterogeneity: source of fitness, hurdle for therapy. Mol Cell. 2015;60:537–46.

    Article  CAS  PubMed  Google Scholar 

  97. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    Article  CAS  PubMed  Google Scholar 

  98. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5:5–23.

    Article  CAS  PubMed  Google Scholar 

  100. Fu NY, Nolan E, Lindeman GJ, Visvader JE. Stem cells and the differentiation hierarchy in mammary gland development. Physiol Rev. 2020;100:489–523.

    Article  CAS  PubMed  Google Scholar 

  101. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Prim. 2019;5:66.

    Article  PubMed  Google Scholar 

  102. Metser G, Shin HY, Wang C, Yoo KH, Oh S, Villarino AV, et al. An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic Acids Res. 2016;44:1052–63.

    Article  CAS  PubMed  Google Scholar 

  103. Yoo KH, Oh S, Kang K, Hensel T, Robinson GW, Hennighausen L. Loss of EZH2 results in precocious mammary gland development and activation of STAT5-dependent genes. Nucleic Acids Res. 2015;43:8774–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Peri S, de Cicco RL, Santucci-Pereira J, Slifker M, Ross EA, Russo IH, et al. Defining the genomic signature of the parous breast. BMC Med Genomics. 2012;5:46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Russo J, Santucci-Pereira J, de Cicco RL, Sheriff F, Russo PA, Peri S, et al. Pregnancy-induced chromatin remodeling in the breast of postmenopausal women. Int J Cancer. 2012;131:1059–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Thankachan S, Bhardwaj BK, Venkatesh T, Suresh PS. Long non-coding RNA NEAT1 as an emerging biomarker in breast and gynecologic cancers: a systematic overview. Reprod Sci. 2021. https://doi.org/10.1007/s43032-021-00481-x.

  107. Li W, Zhang Z, Liu X, Cheng X, Zhang Y, Han X, et al. The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. J Clin Invest. 2017;127:3421–40.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Arshi A, Sharifi FS, Khorramian Ghahfarokhi M, Faghih Z, Doosti A, Ostovari S, et al. Expression analysis of MALAT1, GAS5, SRA, and NEAT1 lncRNAs in breast cancer tissues from young women and women over 45 years of age. Mol Ther Nucleic Acids. 2018;12:751–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ghafouri-Fard S, Taheri M, Omrani MD, Kholghi Oskooei V. Expression of long noncoding RNAs in breast cancer in relation to reproductive factors and tumor characteristics. J Cell Biochem. 2019;120:13965–73.

    Article  CAS  PubMed  Google Scholar 

  110. Li X, Deng S, Pang X, Song Y, Luo S, Jin L, et al. LncRNA NEAT1 silenced miR-133b promotes migration and invasion of breast cancer cells. Int J Mol Sci. 2019;20:3616.

  111. Liu X, Yao W, Xiong H, Li Q, Li Y. LncRNA NEAT1 accelerates breast cancer progression through regulating miR-410-3p/ CCND1 axis. Cancer Biomark. 2020;29:277–90.

    Article  CAS  PubMed  Google Scholar 

  112. Pang Y, Wu J, Li X, Wang C, Wang M, Liu J, et al. NEAT1/miR124/STAT3 feedback loop promotes breast cancer progression. Int J Oncol. 2019;55:745–54.

    CAS  PubMed  Google Scholar 

  113. Qian K, Liu G, Tang Z, Hu Y, Fang Y, Chen Z, et al. The long non-coding RNA NEAT1 interacted with miR-101 modulates breast cancer growth by targeting EZH2. Arch Biochem Biophys. 2017;615:1–9.

    Article  CAS  PubMed  Google Scholar 

  114. Zhang M, Wu WB, Wang ZW, Wang XH. lncRNA NEAT1 is closely related with progression of breast cancer via promoting proliferation and EMT. Eur Rev Med Pharm Sci. 2017;21:1020–6.

    CAS  Google Scholar 

  115. Zhao D, Zhang Y, Wang N, Yu N. NEAT1 negatively regulates miR-218 expression and promotes breast cancer progression. Cancer Biomark. 2017;20:247–54.

    Article  CAS  PubMed  Google Scholar 

  116. Idogawa M, Nakase H, Sasaki Y, Tokino T. Prognostic effect of long noncoding RNA NEAT1 expression depends on p53 mutation status in cancer. J Oncol. 2019;2019:4368068.

    PubMed  PubMed Central  Google Scholar 

  117. Li X, Wang S, Li Z, Long X, Guo Z, Zhang G, et al. The lncRNA NEAT1 facilitates cell growth and invasion via the miR-211/HMGA2 axis in breast cancer. Int J Biol Macromol. 2017;105:346–53.

    Article  CAS  PubMed  Google Scholar 

  118. Muller V, Oliveira-Ferrer L, Steinbach B, Pantel K, Schwarzenbach H. Interplay of lncRNA H19/miR-675 and lncRNA NEAT1/miR-204 in breast cancer. Mol Oncol. 2019;13:1137–49.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Shin VY, Chen J, Cheuk IW, Siu MT, Ho CW, Wang X, et al. Long non-coding RNA NEAT1 confers oncogenic role in triple-negative breast cancer through modulating chemoresistance and cancer stemness. Cell Death Dis. 2019;10:270.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Zhou D, Gu J, Wang Y, Wu H, Cheng W, Wang Q, et al. Long non-coding RNA NEAT1 transported by extracellular vesicles contributes to breast cancer development by sponging microRNA-141-3p and regulating KLF12. Cell Biosci. 2021;11:68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Swellam M, El Magdoub HM, Shawki MA, Adel M, Hefny MM, El-Shazly SS. Clinical impact of LncRNA XIST and LncRNA NEAT1 for diagnosis of high-risk group breast cancer patients. Curr Probl Cancer. 2021. https://doi.org/10.1016/j.currproblcancer.2021.100709.

  122. Brancolini C, Iuliano L. Proteotoxic stress and cell death in cancer cells. Cancers. 2020;12:2385.

  123. de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020;130:5074–87.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7:1016–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  126. Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010;2010:214074.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Santagata S, Hu R, Lin NU, Mendillo ML, Collins LC, Hankinson SE, et al. High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci USA. 2011;108:18378–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Jiang X, Zhou Y, Sun AJ, Xue JL. NEAT1 contributes to breast cancer progression through modulating miR-448 and ZEB1. J Cell Physiol. 2018;233:8558–66.

    Article  CAS  PubMed  Google Scholar 

  129. Xiong Y, Liu Z, Li Z, Wang S, Shen N, Xin Y, et al. Long noncoding RNA nuclear paraspeckle assembly transcript 1 interacts with microRNA107 to modulate breast cancer growth and metastasis by targeting carnitine palmitoyltransferase1. Int J Oncol. 2019;55:1125–36.

    CAS  PubMed  Google Scholar 

  130. Ke H, Zhao L, Feng X, Xu H, Zou L, Yang Q, et al. NEAT1 is required for survival of breast cancer cells through FUS and miR-548. Gene Regul Syst Bio. 2016;10:11–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Lo PK, Zhang Y, Wolfson B, Gernapudi R, Yao Y, Duru N, et al. Dysregulation of the BRCA1/long non-coding RNA NEAT1 signaling axis contributes to breast tumorigenesis. Oncotarget. 2016;7:65067–89.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Lin LC, Lee HT, Chien PJ, Huang YH, Chang MY, Lee YC, et al. NAD(P)H:quinone oxidoreductase 1 determines radiosensitivity of triple negative breast cancer cells and is controlled by long non-coding RNA NEAT1. Int J Med Sci. 2020;17:2214–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Morotti M, Bridges E, Valli A, Choudhry H, Sheldon H, Wigfield S, et al. Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer. Proc Natl Acad Sci USA. 2019;116:12452–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Isobe M, Toya H, Mito M, Chiba T, Asahara H, Hirose T, et al. Forced isoform switching of Neat1_1 to Neat1_2 leads to the loss of Neat1_1 and the hyperformation of paraspeckles but does not affect the development and growth of mice. RNA. 2020;26:251–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ilinskaya O, Hausenloy DJ, Cabrera-Fuentes HA, Zenkova M. Editorial: New advances in RNA targeting. Front Pharmacol. 2020;11:468.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Sheridan C. First small-molecule drug targeting RNA gains momentum. Nat Biotechnol. 2021;39:6–8.

    Article  CAS  PubMed  Google Scholar 

  138. Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov. 2021. https://doi.org/10.1038/s41573-021-00219-z.

  139. Chen Y, Li Z, Chen X, Zhang S. Long non-coding RNAs: from disease code to drug role. Acta Pharm Sin B. 2021;11:340–54.

    Article  CAS  PubMed  Google Scholar 

  140. Abulwerdi FA, Xu W, Ageeli AA, Yonkunas MJ, Arun G, Nam H, et al. Selective small-molecule targeting of a triple helix encoded by the long noncoding RNA, MALAT1. ACS Chem Biol. 2019;14:223–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Donlic A, Zafferani M, Padroni G, Puri M, Hargrove AE. Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans. Nucleic Acids Res. 2020;48:7653–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yao L, Chen L, Zhou H, Duan F, Wang L, Zhang Y. Long noncoding RNA NEAT1 promotes the progression of breast cancer by regulating miR-138-5p/ZFX axis. Cancer Biother Radiopharm. 2020. https://doi.org/10.1089/cbr.2019.3515.

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Funding

This work was supported by Northern Norway Regional Health Authority grants to EK (HNF1522-20) and MP (HNF1546-20). ALH is supported by Breast Cancer Research Foundation and Cancer Research UK.

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  1. Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037, Tromsø, Norway

    Erik Knutsen & Maria Perander

  2. Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK

    Adrian L. Harris

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  1. Erik Knutsen
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  2. Adrian L. Harris
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EK, ALH and MP conceptualised and wrote the manuscript.

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Correspondence to Maria Perander.

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Knutsen, E., Harris, A.L. & Perander, M. Expression and functions of long non-coding RNA NEAT1 and isoforms in breast cancer. Br J Cancer 126, 551–561 (2022). https://doi.org/10.1038/s41416-021-01588-3

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