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Roles of lncRNA in the diagnosis and prognosis of triple-negative breast cancer
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Review | Updated:2024-01-19
    • Roles of lncRNA in the diagnosis and prognosis of triple-negative breast cancer

    • LncRNA在三阴性乳腺癌诊断和预后中的作用
    • Qiuhui YANG

      ,   ,  

      Yeqin FU

      ,   ,  

      Jiaxuan WANG

      ,   ,  

      Hongjian YANG

      ,   ,  

      Xiping ZHANG

      ,   ,  
    • Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology)   Vol. 24, Issue 12, Pages: 1123-1140(2023)
    • DOI:10.1631/jzus.B2300067    

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  • Qiuhui YANG, Yeqin FU, Jiaxuan WANG, et al. Roles of lncRNA in the diagnosis and prognosis of triple-negative breast cancer. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 24(12):1123-1140(2023) DOI: 10.1631/jzus.B2300067.

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    Abstract

    Breast cancer is a malignant tumor that seriously endangers women’s lives. The prognosis of breast cancer patients differs among molecular types. Compared with other subtypes, triple-negative breast cancer (TNBC) has been a research hotspot in recent years because of its high degree of malignancy, strong invasiveness, rapid progression, easy of recurrence, distant metastasis, poor prognosis, and high mortality. Many studies have found that long non-coding RNA (lncRNA) plays an important role in the occurrence, proliferation, migration, recurrence, chemotherapy resistance, and other characteristics of TNBC. Some lncRNAs are expected to become biomarkers in the diagnosis and prognosis of TNBC, and even new targets for its treatment. Based on a PubMed literature search, this review summarizes the progress in research on lncRNAs in TNBC and discusses their roles in TNBC diagnosis, prognosis, and chemotherapy with the hope of providing help for future research.

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    摘要

    乳腺癌是一种严重危害女性生命的恶性肿瘤。乳腺癌患者的预后因分子类型而异,与其它亚型相比,三阴性乳腺癌(TNBC)因其恶性程度高、侵袭性强、进展快、易复发、易远处转移、预后差和死亡率高而成为近年来的研究热点。许多研究发现,长链非编码RNAs(lncRNAs)在TNBC的发生、增殖、迁移、复发和化疗耐药性等方面起着重要作用。一些lncRNAs有望成为TNBC诊断和预后判断的生物学标志物,甚至成为治疗的新靶点。本文在PubMed文献检索的基础上,总结了lncRNAs在TNBC中的研究进展,并讨论了它们在TNBC诊断、预后和化疗中的作用,希望为未来的研究提供帮助。

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    关键词

    三阴性乳腺癌(TNBC); 长链非编码RNA(lncRNA); 诊断; 预后; 化疗耐药

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    Keywords

    Triple-negative breast cancer (TNBC); Long non-coding RNA (lncRNA); Diagnosis; Prognosis; Chemotherapy resistance

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    1 Introduction

    The latest data for 2020 released by the World Health Organization (WHO)’s International Agency for Research on Cancer (IARC) show that breast cancer has officially replaced lung cancer as the cancer with the highest morbidity rate worldwide. Breast cancer is a serious health risk for women as it affects one in eight newly diagnosed cancer patients. In addition, as women age, the incidence and mortality rate of breast cancer increase (

    Chen et al., 2017; Zaheer et al., 2019). Breast cancer is now the most prevalent cancer among women in China (Cao et al., 2021).
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    Breast cancer can usually be classified according to the expression levels of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her-2/neu), and Ki-67 (

    Prat et al., 2015; Santamaría et al., 2019). Breast cancer lacking ER, PR, and Her-2 is a highly invasive clinical subtype called triple-negative breast cancer (TNBC) (Carey et al., 2010; Borri and Granaglia, 2021). TNBC accounts for 10%‍‒‍25% of breast cancers and tends to have a higher incidence among young people than other cancers (Shen et al., 2015; Kumar and Aggarwal, 2016). At present, the main treatment strategies for TNBC are chemotherapy, surgery, and radiotherapy (Abramson et al., 2015). Although relevant studies have confirmed that TNBC patients can achieve a high pathological complete response after chemotherapy, the lack of therapeutic targets for Her-2 and hormone receptors combined with the high heterogeneity of this tumor type makes TNBC more aggressive, with earlier recurrence and distant metastases (Manjunath and Choudhary, 2021).
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    To treat TNBC patients more accurately and efficiently, previous studies analyzed the gene expression profile of tumor samples from 587 TNBC patients and found that TNBC can be divided into six subtypes: basal-like subtype 1 (BL1), BL2, mesenchymal (M), mesenchymal stem cell-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR) subtypes (

    Lehmann et al., 2011; Vtorushin et al., 2022). Furthermore, Zhao et al. (2020) developed a set of Fudan typing standards for TNBC, which divided TNBC into a basal-like immunosuppressive subtype (BLIS), IM, LAR, and mesenchymal-like subtype (MES). In the meantime, investigators invented a set of immunohistochemistry (IHC)-based classifiers, providing a simpler and more economical typing method that can benefit more TNBC patients. A more precise classification of the disease would allow patients to benefit more from individualized treatment.
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    Protein-coding genes account for about 2% of the human genome sequence, and the rest are non-coding sequences (

    Djebali et al., 2012). Non-coding sequences were originally considered “dark matter” or “garbage.” However, increasing evidence shows that non-coding RNA (ncRNA) plays an important role in the process of metabolism and development, and can participate in the regulation of gene expression, including transcriptional, post-transcriptional, translational, and epigenetic regulation (Kumar et al., 2013). Moreover, it plays a key role in the regulation of cancer’s biological characteristics. Long non-coding RNA (lncRNA) is a ncRNA that consists of at least 200 nucleotides (nt) but lacks the function of encoding protein (Liu et al., 2017). An abnormal expression level of lncRNA is related to various malignant biological processes, including tumorigenesis, proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), and distant metastasis (Fu PF et al., 2019). In recent years, many studies have found significant differences in the expression level of lncRNA in the tumors and blood of TNBC patients compared to normal controls (Xu et al., 2020; Qu et al., 2022). Therefore, it is inferred that lncRNA can be used as a diagnostic or prognostic marker for TNBC patients. In this paper, we summarize recent lncRNA research related to the diagnosis and prognosis of TNBC, and analyze the prospects and feasibility for its application in this field.
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    2 LncRNAs with diagnostic and prognostic functions

    2.1 LncRNAs with diagnostic functions for TNBC

    Early diagnosis of TNBC is the key to effective treatment. At present, the diagnosis of TNBC relies mainly on the IHC results of the patient’s tumor tissue, and sometimes requires additional testing with fluorescence in situ hybridization (FISH) for those with Her-2 low expression, which is time-consuming and costly. However, with the rapid development of gene sequencing technology, the detection of ncRNA has become easier and more economical. Many studies have found abnormal expression of lncRNA in TNBC tissues, suggesting that lncRNA could be useful as a marker for the diagnosis of TNBC. For example,

    Swellam et al. (2021) examined the expression of lncRNAs X inactive-specific transcript (XIST) and nuclear paraspeckle assembly transcript 1 (NEAT1) in serum samples from breast cancer patients, benign breast lesion patients, and healthy volunteers by quantitative real-time polymerase chain reaction (qRT-PCR). They found that the expression levels of XIST and NEAT1 were significantly higher in the breast cancer group than in the other two groups. The expression levels were higher in TNBC, which could be used to distinguish TNBC from other breast cancer types. In addition, Liu et al. (2017) performed microarray analysis of plasma from 25 TNBC patients and 35 non-TNBC (NTNBC) patients and found that the expression levels of the lncRNAs antisense ncRNA in the INK4 locus (ANRIL), hypoxia-inducible factor 1α‍antisense RNA-2 (HIF1A-AS2), and urothelial carcinoma-associated 1 (UCA1) were significantly higher in the plasma of TNBC patients than in that of the NTNBC group. The result was verified in tumor tissues, suggesting that these three genes can be used to distinguish TNBC from NTNBC. The researchers further developed a TNBC SigLnc-3 regression equation based on the above three genes, which showed excellent diagnostic performance in a validation set with an area under the curve (AUC) of 0.934, which was superior to the diagnostic effects of ANRIL, HIF1A-AS2, and UCA1 alone. However, not all lncRNAs are overexpressed in TNBC tissues. For instance, lncRNA ZNFX1 antisense RNA 1 (ZFAS1) is significantly under-expressed in the blood of TNBC patients, at about 1/3 of the blood level of a normal group, and the decreased expression can be used to diagnose TNBC (Sharma et al., 2021) (Table 1).
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    Table 1  LncRNAs related to the diagnosis of TNBC
    LncRNAChangeSourceNumber of patientsPopulation studyMethodReference
    XIST, NEAT1 Up Serum 178 TNBC and HC qRT-PCR Swellam et al., 2021
    ANRIL, HIF1A-AS2, UCA1 Up Plasma, tumor 60 TNBC and NTNBC MA and PCR Liu et al., 2017
    ZFAS1 Down Blood 80 TNBC and HC qRT-PCR Sharma et al., 2021

    LncRNA: long non-coding RNA; TNBC: triple‍-‍negative breast cancer; XIST: X inactive-specific transcript; NEAT1: nuclear paraspeckle assembly transcript 1; ANRIL: antisense non-coding RNA in the INK4 locus; HIF1A-AS2: hypoxia-inducible factor 1α‍-antisense RNA-2; UCA1: urothelial carcinoma-associated 1; ZFAS1: ZNFX1 antisense RNA 1; HC: healthy control; NTNBC: non-TNBC; PCR: polymerase chain reaction; qRT-PCR: quantitative real-time PCR; MA: microarray analysis.

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    2.2 LncRNAs to predict the prognosis of TNBC

    TNBC is the worst pathological type of breast cancer with higher invasiveness, recurrence, and distant metastasis rates. It can be divided into different subtypes with different prognoses. If the prognosis of the disease can be understood at an early stage, patients can be treated better and their prognosis can be improved.

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    He et al. (2023) analyzed the relationship between the expression of lncRNA T376626 in the serum of 282 breast cancer patients and the overall survival (OS) rate by the Kaplan-Meier (K-M) method. They found that in breast cancer and TNBC patients, a higher level of T376626 was positively correlated with a higher stage of pathological differentiation, more aggressive molecular subtypes, and poorer prognosis. Moreover, by comparing the levels of serum extracellular vesicle lncRNA XIST between TNBC patients (n=91) and a healthy control group (n=50), they found that the expression level was significantly higher in the TNBC group than in the control group, and was significantly increased in TNBC recurrent patients. After tumor resection, the serum XIST content decreased. Results from the survival analysis showed that the higher the serum XIST content, the worse the patient’s prognosis, indicating that XIST can be used as a prognostic indicator for TNBC patients (Lan et al., 2021). The blood contains tumor markers that may be produced by the death of tumor cells or by autocrine production of tumor cells. It is less invasive and more convenient to diagnose patients through blood biopsy.
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    In addition to blood, the level of gene expression can be measured in tumor tissue to reflect a patient’s prognosis. For example, by analyzing 1085 TNBC tumor samples and 291 matched normal control samples from The Cancer Genome Atlas (TCGA) database,

    Sharma et al. (2021) found that the OS of breast cancer patients with a low expression of lncRNA ZFAS1 was lower than that of a high expression group, and the expression of ZFAS1 was positively correlated with the prognosis. Similarly, Kaushik et al. (2021) found 353 lncRNAs significantly different between shorter and longer OS groups by searching the The Atlas of Non-coding RNA in Cancer (TANRIC) database (OS was cut off at three years). Furthermore, using recursive feature elimination analysis, they found that lncRNAs long intergenic ncRNA for kinase activation (LINK-A) LINC01139 and breast cancer anti-estrogen resistance 4 (BCAR4) had high values in predicting a patient’s prognosis. Moreover, Zhang KM et al. (2018) analyzed the relationship between the expression of actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1) and prognosis in 238 TNBC patients. The results showed that patients with high expression of AFAP1-AS1 (n=132) had poorer disease-free survival (DFS) and OS compared to the low expression group (n=106). Their further analysis found that AFAP1-AS1 can activate the Wnt/β‍-catenin pathway, increasing the expression of C-myc and EMT-related molecules to promote tumor cell proliferation and invasion and inhibit cell apoptosis, leading to poor prognosis. LINK-A was also found to be associated with TNBC in several studies. For example, Lin et al. (2016) showed that the expression of LINK-A under normoxic conditions can promote the reprogramming of breast cancer glycolysis and tumorigenesis by activating hypoxia-inducible factor-1α (HIF-1α) signaling. TNBC patients with high LINK-A expression had lower recurrence-free survival (RFS) than a low expression group (n=123). HIF-‍1α can accumulate under normoxic conditions, promoting angiogenesis and cancer progression (Kuschel et al., 2012). It has also been shown that HIF is involved in the progression, recurrence, and metabolic reprogramming of TNBC (Semenza, 2003; Wong et al., 2011). LncRNA differentiation antagonizing non-protein coding RNA (DANCR) can promote the proliferation and invasion of TNBC cells by reducing the expression level of the microRNA-216a-5p (miR-216a-5p) gene. Tao et al. (2019) divided 57 TNBC patients into a high DANCR expression group (n=25) and a low DANCR expression group (n=32), and the results of analysis showed that the OS of the low expression group was significantly higher than that of the high expression group. Compared to normal tissues, lncRNAs LINC01270, LINC00449, and highly upregulated in metastatic TNBC (HUMT) were also all highly expressed in TNBC tumor tissues, and the expression levels were positively correlated with prognostic levels (Zheng SQ et al., 2020; Ping et al., 2021) (Table 2).
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    Table 2  LncRNAs related to the prognosis of TNBC
    LncRNAChangeMechanismOutcomeNumber of patientsPopulation studyMethodReference
    T376626 Up Bind to LAMC2 Poor OS 282 BC/TNBC K-M He et al., 2023
    XIST Up Unknown Poor OS 141 TNBC/NC K-M/Cox Lan et al., 2021
    ZFAS1 Down Inhibit p21 and p27, and promote EMT Poor OS 1376 TNBC/NC TCGA/K-M Sharma et al., 2021
    LINK-A, BCAR4 Up HIF-1α pathway activation Poor RFS 353/123 TNBC TANRIC/Gehan-Breslow test Lin et al., 2016; Kaushik et al., 2021
    AFAP1-AS1 Up Activate Wnt/β-catenin pathway, increase the expression of C-myc and EMT-related molecules Poor OS and DFS 238 TNBC K-M Zhang KM et al., 2018
    DANCR Up Inhibit miR-216a-5p expression Poor OS 57 TNBC K-M Tao et al., 2019
    LINC01270, LINC00449 Up Promote cell invasion and migration Poor OS and DFS 200 TNBC Cox Ping et al., 2021
    HUMT Up Hypomethylation of promoter region Higher TN stage, poor OS and DFS 228 TNBC K-M/log-rank test Zheng SQ et al., 2020

    LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; XIST: X inactive-specific transcript; ZFAS1: ZNFX1 antisense RNA 1; LINK-A: long intergenic non-coding RNA for kinase activation; BCAR4: breast cancer anti-estrogen resistance 4; AFAP1-AS1: actin filament-associated protein 1-antisense RNA 1; DANCR: differentiation antagonizing non-protein coding RNA; HUMT: highly upregulated in metastatic TNBC; LAMC2: laminin gamma 2; EMT: epithelial-mesenchymal transition; HIF-1α: hypoxia-inducible factor-1α; miR: microRNA; OS: overall survival; RFS: recurrence-free survival; DFS: disease-free survival; TN: tumor node; BC: breast cancer; NC: normal control; K-M: Kaplan-Meier; TCGA: The Cancer Genome Atlas; TANRIC: The Atlas of Non-coding RNA in Cancer.

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    3 LncRNAs that promote the progression of TNBC

    In recent years, numerous studies have pointed out that lncRNA is involved in the formation and progression of breast cancer, especially TNBC, which is more heterogeneous. The progression of TNBC is closely related to the biological processes of tumor cell proliferation, invasion, migration, and blood vessel formation. By detecting lncRNA in patients’ tumor tissues or blood, we can judge the malignancy of tumors at an early stage, make relevant interventions, and improve prognoses.

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    3.1 LncRNAs that promote proliferation and invasion of TNBC cells

    LncRNA lung cancer-associated transcript 1 (LUCAT1) plays an important role in the development of TNBC, and its expression level is positively correlated with the prognosis level of TNBC patients.

    Mou and Wang (2019) first discovered that LUCAT1 can bind to miR-5702 and promote the proliferation and migration of TNBC cells. Furthermore, they found that silencing its expression could inhibit the proliferation of TNBC cells and promote apoptosis. LncRNA WEE2-antisense RNA 1 (WEE2-AS1) also plays an instrumental role in the progression of TNBC. An investigation of the mechanism of action of WEE2-AS1 in TNBC by Wang et al. (2020) found that the proliferation and invasion abilities of TNBC cells were inhibited after silencing the highly expressed WEE2-AS1. Moreover, through functional assays, they found that WEE2-AS1 can combine with miR-32-5p and deregulate the repression of transducer of ERBB2.1 (TOB1) by miR-32-5p, leading to upregulation of TOB1 expression and promotion of the proliferation, invasion, and migration of TNBC cells. LncRNA LINC00173 plays a critical role in chemotherapy resistance among small cell lung cancers. In recent years, relevant studies have shown that LINC00173 is also involved in the occurrence and development of TNBC cells. In in vitro studies, Fan et al. (2020) found that TNBC cells with high expression of the LINC00173 gene had stronger proliferation and invasion abilities, which may be mediated by inhibiting the expression of miR-490-3p. Animal experiments showed similar results, with silencing the LINC00173 gene significantly reducing tumor weight (Fan et al., 2020).
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    Compared to their expression in other types of breast cancer, the lncRNAs DANCR, zinc finger E-box binding homeobox 2-antisense RNA 1 (ZEB2-AS1), human ovarian cancer-specific transcript 2 (HOST2), miR-100 host gene (MIR100HG), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and POU class 3 homeobox 3 (POU3F3) are highly expressed in TNBC tissues and cell lines (

    Tang JM et al., 2018; Wang SW et al., 2018; Yang et al., 2019; Zhang GX et al., 2019; Zhang YD et al., 2019). The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway plays a very critical role in the proliferation of TNBC cells (Hatem et al., 2016). Cellular experiments have shown that the DANCR–retinoid X receptor protein α (RXRA)‍–PI3K/AKT signaling axis is involved in TNBC proliferation and invasion. DANCR promotes proliferation and tumorigenesis in TNBC through activating ser49/78 phosphorylation of RXRA, thereby promoting phosphatidylinositol-4,‍5-biophosphate 3-kinase catalytic subunit α (PIK3CA) expression and subsequently enhancing PI3K/AKT signaling, causing TNBC tumorigenesis (Tang JM et al., 2018; Zhang GX et al., 2019). Likewise, lncRNA ‍ZEB2-AS1 is located mainly near ZEB2 in the nucleus and can positively regulate ZEB2 expression and activate EMT via the PI3K/AKT/glycogen synthase kinase 3 β (GSK3β)/ZEB2 signaling pathway to further promote cell proliferation and migration (Zhang GX et al., 2019). MALAT1 is an lncRNA about 8000 nt long, which is widely expressed and highly conserved in mammalian cells. By examining 43 TNBC tissues and paired adjacent non-tumor tissues, it was found that MALAT1 was highly expressed in TNBC tissues, and that highly expressed MALAT1 could promote proliferation, invasion, and cell cycling of TNBC cells, and that this effect might be mediated by MALAT1/miR-129-5p axis (Zuo et al., 2017) (Table 3, Fig. 1).
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    Table 3  LncRNAs that promote the proliferation and invasion of TNBC cells
    LncRNAChangeMechanismOutcomeCellsMethodReference
    LUCAT1 Up Bind tomiR-5702 Progression MCF-10A, TNBC cell lines (231, BT549, 453, and 468) qRT-PCR, CCK-8, Transwell assay, WB, etc. Mou and Wang, 2019
    WEE2-AS1 Up WEE2-AS1/miR-32-5p/TOB1 axis Progression MCF-10A, TNBC cell lines (231, 436, and 468) qRT-PCR, colony formation, Transwell assay, EdU, etc. Wang et al., 2020
    LINC00173 Up SuppressmiR-490-3p Progression TNBC cell lines (231, 468, and BT549) qRT-PCR, colony formation, Transwell assay, cell proliferation assay Fan et al., 2020
    DANCR Up DANCR–RXRA–PI3K/AKT Progression TNBC cell lines (BT549, MCF-7, T47D, 231, 453, and 468) RT-qPCR, ChIP-qPCR, luciferase promoter assay, RIP, colony formation, etc. Tang JM et al., 2018
    ZEB2-AS1 Up PI3K/AKT/GSK3β/ZEB2 Progression MCF‐10A, TNBC cell lines (T47D, MCF‐7, 435, and 231) Wound healing, CCK-8, Transwell assay, qRT-PCR, etc. Zhang GX et al., 2019
    MALAT1 Up Bind tomiR-129-5p Progression MCF-10A, TNBC cell lines (231, 453, MCF-7, BT549, and BT474) qRT-PCR, CCK-8, flow cytometry analysis, scratch assay, Transwell assay, etc. Zuo et al., 2017
    HOST2 Up Let-7b/CDK6 axis Progression MCF-10A, TNBC cell lines (231 and 468) RT-qPCR, WB, flow cytometry with PI staining, CCK-8, etc. Zhang YD et al., 2019
    MIR100HG Up Inhibit p27 protein Progression TNBC cell lines (231 and BT549) RT-qPCR, MTS assay, flow cytometry, BrdU, etc. Wang SW et al., 2018
    POU3F3 Up Downregulate Caspase-9 Progression TNBC cell lines (231 and BT20) RT-qPCR, CCK-8, cell apoptosis assay, WB, etc. Yang et al., 2019

    LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; LUCAT1: lung cancer-associated transcript 1; WEE2-AS1: WEE2-antisense RNA 1; DANCR: differentiation antagonizing non-protein coding RNA; ZEB2-AS1: zinc finger E-box binding homeobox 2-antisense RNA 1; MALAT1: metastasis-associated lung adenocarcinoma transcript 1; HOST2: human ovarian cancer-specific transcript 2; MIR100HG: miR-100 host gene; POU3F3: POU class 3 homeobox 3; miR: microRNA; TOB1: transducer of ERBB2.1; RXRA: retinoid X receptor protein α; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; GSK3β: glycogen synthase kinase 3 β; CDK6: cyclin-dependent kinase 6; 231: MDA-MB-231; 453: MDA-MB-453; 468: MDA-MB-468; 436: MDA-MB-436; 435: MDA-MB-435; qRT-PCR, qPCR: quantitative real-time polymerase chain reaction; RT-qPCR: reverse transcription-qPCR; CCK-8: cell counting kit‐‍8; WB: western blotting; EdU: 5-ethynyl-20-deoxyuridine; ChIP: chromatin immunoprecipitation; RIP: RNA immunoprecipitation; MTS: mitochondrial-targeting sequence; PI: propidium iodide; BrdU: bromodeoxyuridine.

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    Fig. 1  Diagram of the mechanisms by which lncRNAs promote proliferation and invasion of TNBC cells. LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; LUCAT1: lung cancer-associated transcript 1; miR: microRNA; DANCR: differentiation antagonizing non-protein coding RNA; RXRA: retinoid X receptor protein α; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; WEE2-AS1: WEE2-antisense RNA 1; TOB1: transducer of ERBB2.1; mRNA: messenger RNA; POU3F3: POU class 3 homeobox 3.

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    In summary, the above lncRNAs are highly expressed in TNBC tissues or plasma and can promote tumor cell proliferation and invasion through different mechanisms. Silencing lncRNAs or their downstream key molecules can inhibit the proliferation and speed of invasion of TNBC cells, and even cause cell death due to the lack of relevant growth factors. Thus, this technology is expected to be applied in the clinic for the benefit of TNBC patients.

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    3.2 LncRNAs that promote TNBC cell metastasis

    Metastasis refers to the process of malignant tumor cells leaving the primary site and arriving at tissues that are not contiguous with the primary site through various transport pathways, to continue to grow and form secondary tumors with the same pathological properties as the primary tumor. Metastasis is a multi-step and multi-factorial process linked to gene regulation, signaling pathways, and cellular junctions. LncRNA, as an important component of non-coding RNA, has been found to play an important role in cancer metastasis.

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    The immune system is able to exert anti-tumor effects by recognizing antigens on the surface of tumor cells. However, some studies have shown that tumor cells are able to evade the immune system through certain mechanisms preventing the body from producing effective anti-tumor effects and allowing cancer cells to continue to spread. For example,

    Hu et al. (2019) found that high expression of LINK-A in TNBC cells promoted the degradation of peptide-loading complex (PLC) and the intrinsic tumor suppressor genes Retinoblastoma (Rb) and p53, causing the tumor to lose its antigenicity and hence evade the body’s immune examination and facilitate the migration of tumor cells. The main distant metastatic sites of TNBC are the lung, brain, liver, and bone (Foulkes et al., 2010). Wang PS et al. (2018) found via Transwell assay that the metastatic ability of TNBC cells with high expression of linc-zinc finger 469-3 (linc-ZNF469-3) was 4.1-fold higher than that of a control group (P<0.05). After injecting this gene into mice, they found that the mice showed more and larger metastatic tumors in the lungs compared with the control group, suggesting that linc-ZNF469-3 could function as a potential metastatic marker in TNBC patients. This biological function may act through the linc-ZNF469-3/miR-574-5p/ZEB1 axis. Lin et al. (2018) found that the lncRNA HIF1A-AS2 can promote colorectal cancer cell (CRC) proliferation, invasion, and EMT formation via the miR-129-5p/DNA (cytosine-5)-methyltransferase 3A (DNMT3A) axis. Wang YF et al. (2019) found that the expression of HIF1A-AS2 was significantly elevated in TNBC cell lines compared with normal mammary epithelial cell lines. Besides, silencing the expression of HIF1A-AS2 significantly inhibited the migration and invasion of TNBC cells. In addition, basic data showed that high expression of HIF1A-AS2 was associated with lymph node metastasis, distant metastasis, and poor histological grading in TNBC patients. Similarly, the expression of the highly up-regulated in liver cancer (HULC) gene is also associated with the migration of TNBC cells and can exert biological functions by regulating the activity of the matrix metalloproteinase-2 (MMP-2)/MMP-9 gene, which has the potential ability to determine whether TNBC patients have metastasis at an early stage (Shi et al., 2016) (Table 4, Fig. 2).
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    Table 4  LncRNAs that promote TNBC cell metastasis
    LncRNAChangeMechanismEffectCellsMethodReference
    LINK-A Up Enhance PLC,Rb, and p53 degradation Metastasis MCF-10A, TNBC cell lines (231, 468, BT549, and HCC1187) Flow cytometry, mass spectrometry, etc. Hu et al., 2019
    Linc-ZNF469-3 Up Linc-ZNF469-3/miR-574-5p/ZEB1 axis Metastasis TNBC cell lines (231, 361, 157, MCF-7, BT483, AU565, SKBR3, BT549, etc.) qRT-PCR, RNA-seq, Transwell assay, soft-agar assay, sphere formation assay, etc. Wang PS et al., 2018
    HIF1A-AS2 Up Unknown Metastasis MCF‐10A, DU4475, HCC1806, and 468 qRT-PCR, Transwell assay Wang YF et al., 2019
    HULC Up Upregulate MMP-2 and MMP-9 Metastasis MCF‐10A, TNBC cell lines(231, 468, BT549, and BT483) qRT-PCR, standard MTT assay, Transwell assay, and WB Shi et al., 2016

    LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; LINK-A: long intergenic non-coding RNA for kinase activation; ZNF469-3: zinc finger 469-3; HIF1A-AS2: hypoxia-inducible factor 1α-antisense RNA 2; HULC: highly up-regulated in liver cancer; PLC: peptide-loading complex; Rb: retinoblastoma; miR: microRNA; ZEB1: zinc finger E-box binding homeobox 1; MMP: matrix metalloproteinase; 231: MDA-MB-231; 468: MDA-MB-468; 361: MDA-MB-361; 157: MDA-MB-157; HCC: hepatocellular carcinoma; qRT-PCR: quantitative real-time polymerase chain reaction; RNA-seq: RNA sequencing; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; WB: western blotting.

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    Fig. 2  Diagram of the mechanisms by which lncRNAs promote TNBC cell metastasis. LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; LINK-A: long intergenic non-coding RNA for kinase activation; PLC: peptide-loading complex; Rb: retinoblastoma; ZNF469-3: zinc finger 469-3; miR: microRNA; ZEB1: zinc finger E-box binding homeobox 1; HULC: highly up-regulated in liver cancer; MMP: matrix metalloproteinase.

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    Distant metastasis is the leading cause of death and the most serious complication for cancer patients. Currently, patients with distant metastases are largely losing their chance for surgical treatment, and median survival is measured in months. The above studies found that by silencing metastasis-related lncRNAs, the migration ability of TNBC cells could be weakened, reducing the risk of distant metastasis and prolonging the survival of patients.

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    4 LncRNAs that inhibit the progression of TNBC

    We found that lncRNA mainly plays a promotional role in tumor formation and development, and only a small number of lncRNAs play a role in inhibiting tumor formation and attenuating cell proliferation, invasion, and migration. These lncRNAs show low expression in TNBC tissues or cells.

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    For example,

    Sharma et al. (2021) found that lncRNA ZFAS1 was differentially expressed in the plasma of TNBC patients versus normal individuals and could be used as a diagnostic marker for TNBC. After further analysis, they found that silencing the ZFAS1 gene enhanced the EMT capacity of TNBC cells by inhibiting the expression of the cyclin-dependent kinase (CDK) inhibitors p21 (CDKN1A) and p27 (CDKN1B). This promoted the proliferation and migration of TNBC cells, leading to poorer prognoses (Sharma et al., 2021). In addition, lncRNA can exert biological effects by interacting with downstream microRNAs (miRNAs). For instance, lncRNA miR-503 host gene (MIR503HG) is able to inhibit cell migration and invasion via the miR-103/olfactomedin 4 (OLFM4) axis in TNBC cells, and low expression of MIR503HG is associated with clinically advanced stage, lymph node metastasis, and distant metastasis (Fu J et al., 2019).
    transl

    Moreover, overexpression of lncRNA acetylserotonin O-methyltransferase-like-antisense RNA 1 (ASMTL-AS1) can reduce the colony formation, activity, and invasion ability of TNBC cells by more than 2.5 times. RNA pull-down and luciferase reporter gene analysis showed that miR-1228-3p directly combined with ASMTL-AS1, and ASMTL-AS1 increased the expression of SRY-box transcription factor 17 (SOX17) by absorbing and inhibiting miR-1228-3p. Subsequently, the upregulated SOX17 trans-suppressed β‍-catenin expression, resulting in the inactivation of carcinogenic Wnt/β‍-catenin signaling, thereby restraining TNBC cell growth and dissemination. Similar results have been observed in mouse tumorigenesis experiments (

    Sun J et al., 2021). Furthermore, lncRNA tumor suppressor candidate 7 (TUSC7) has been characterized as a tumor suppressor in osteosarcoma and colorectal cancers, but whether it also acts as an oncogenic suppressor in TNBC is unclear. Zheng et al. (2021) retrospectively found that low expression of TUSC7 was an independent prognostic factor for poor OS in TNBC patients. Moreover, they found that TUSC7 may silence the mitogen-activated protein kinase (MAPK), PI3K/AKT, and nuclear factor-‍κB (NF-‍κB) signaling pathways by binding to miR-1224-3p, inhibiting TNBC cell growth and metastasis in vitro and in vivo. LncRNA cardiac mesoderm enhancer-associated ncRNA (CARMN) is a host gene for miR-143-3p, and is able to downregulate the expression of the DNA replication initiation factor minichromosome maintenance complex component 5 (MCM5) by producing miR-143-3p, leading to the repression of DNA replication (Sheng et al., 2021). Transwell experiments by Song et al. (2019) showed that overexpression of lncRNA neighboring enhancer of FOXA2 (NEF) can inhibit the migration and invasion of TNBC cells, while cell counting kit‐8 (CCK-8) experiment results showed that NEF has no significant effect on the proliferation of TNBC cells. The above biological behavior may be caused by the negative regulation of miR-155 by NEF. The mechanism of action of lncRNA can involve interactions in addition to those with miRNA. For instance, lncRNA H19 is significantly upregulated in TNBC tissue, and H19 has the ability to promote TNBC cell proliferation. Wang N et al. (2019) found that low expression of lncRNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) can promote the proliferation of TNBC cells by increasing the expression of the H19 gene, but has no significant effect on the migration or invasion of cancer cells. Long non‐‍coding Kelch domain containing 7B (LncKLHDC7B) and lncRNA rhabdomyosarcoma 2-associated transcript (RMST) are weakly expressed in TNBC cells or tissues, and the lower the expression, the worse the invasiveness of cells and patient prognosis. However, the specific mechanism of action is still unclear and further exploration is needed (Wang L et al., 2018; Beltrán-Anaya et al., 2019). LncRNAs TCONS_l2_00002973 and RMST are lowly expressed in TNBC tissues. With low expression, the prognosis of patients is worse, but the exact mechanism of action is still unclear and further investigation is needed (Table 5).
    transl

    Table 5  LncRNAs that inhibit the progression of TNBC
    LncRNAChangeMechanismEffectCellsMethodReference
    ZFAS1 Down Inhibit p21 and p27, and promote EMT Progression 231 qRT-PCR, MTT assay, colony-forming assay, etc. Sharma et al., 2021
    MIR503HG Down miR-103/OLFM4 axis Progression MCF‐10A, 231, and BT549 RT-PCR, luciferase reporter assay, Transwell assay, and WB Fu J et al., 2019
    ASMTL-AS1 Down miR-1228-3p/SOX17/β-catenin Progression 231 and 468 qRT-PCR, colony formation, CCK-8, Transwell assay, etc. Sun J et al., 2021
    TUSC7 Down Regulate the MAPK, PI3K/AKT, and NF-κB signaling pathways Progression 468 RT-qPCR, CCK-8, etc. Zheng et al., 2021
    CARMN Down DownregulatemiR-143-3p and upregulate MCM5 Progression MCF‐10A, 231, and 468 RT-qPCR, CCK-8, colony formation, cell cycle, apoptosis assay, etc. Sheng et al., 2021
    NEF Down UpregulatemiR-155 Progression BT20 and 231 RT-qPCR, CCK-8, Transwell assay, etc. Song et al., 2019
    PTCSC3 Down Upregulate of lncRNA H19 Progression BT549 and HCC70 RT-qPCR, CCK-8, etc. Wang N et al., 2019
    LncKLHDC7B Down Unknown Progression MCF-10A, TNBC cell lines (BT20, 468, and 231), Hs578T, MCF‐7, HCC1187 RT-qPCR, CCK-8, Transwell assay, and apoptosis assay Beltrán-Anaya et al., 2019
    RMST Down Unknown Progression MCF‐10A, MCF-7, AU565, TNBC cell lines (BT20 and BT549) qRT-PCR, CCK-8, colony formation, TUNEL assay, Transwell assay, etc. Wang L et al., 2018

    LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; miR: microRNA; ZFAS1: ZNFX1 antisense RNA 1; MIR503HG: miR-503 host gene; ASMTL-AS1: acetylserotonin O-methyltransferase-like (ASMTL)‍‍-antisense RNA 1; TUSC7: tumor suppressor candidate 7; CARMN: cardiac mesoderm enhancer-associated non-coding RNA; NEF: neighboring enhancer of FOXA2; PTCSC3: papillary thyroid carcinoma susceptibility candidate 3; LncKLHDC7B: long non-coding Kelch domain containing 7B; RMST: rhabdomyosarcoma 2-associated transcript; EMT: epithelial-mesenchymal transition; OLFM4: olfactomedin 4; SOX17: SRY-box transcription factor 17; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; NF-κB: nuclear factor-‍κB; MCM5: minichromosome maintenance complex component 5; 231: MDA-MB-231; 468: MDA-MB-468; qRT-PCR: quantitative real-time polymerase chain reaction (PCR); RT-PCR: reverse transcription-PCR; RT-qPCR: reverse transcription-quantitative PCR; MTT: 3-‍(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; WB: western blotting; CCK-8: cell counting kit‐8; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

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    In summary, all of the above lncRNAs can play a role in inhibiting TNBC cell formation and progression. Some of them play important oncogenic roles not only in TNBC, but also in other cancers. Because a lower expression of lncRNAs in TNBC tissues is associated with a worse prognosis for patients, we could use upregulation of genes to inhibit cancer development and improve patient prognosis.

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    5 Relationship between lncRNAs and chemotherapy resistance

    Chemotherapy is one of the main treatments for TNBC patients. Unfortunately, chemotherapy resistance is very common in TNBC patients and is a major cause of treatment failure (Nedeljković and Damjanović, 2019;

    Yu et al., 2022).
    transl

    Genomic instability (GIN) is crucial to modulating tumor drug resistance. miR-26a-5p is an upstream parameter that regulates GIN. When miR-26a-5p expression is increased, TNBC cells are more sensitive to paclitaxel, whereas silencing the expression of miR-26a-5p promotes autophagy and the emergence of drug resistance in cells. Furthermore,

    Li et al. (2021) identified the upstream regulator lncRNA ovarian tumor domain-containing 6B-antisense RNA 1 (OTUD6B-AS1) of miR-26a-5p through bioinformatics analysis and explored an OTUD6B-AS1/miR-26a-5p/metadherin (MTDH) signal axis regulating TNBC cell resistance through cytological, molecular, and zoological experiments.
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    The expression level of lncRNA H19 was significantly increased in paclitaxel-resistant TNBC cells compared with paclitaxel-sensitive cells. H19 can not only promote the proliferation of TNBC cells, but also inhibit apoptosis and promote paclitaxel resistance in TNBC cells by activating the AKT signaling pathway (

    Han et al., 2018). Jiang et al. (2016) found that the half maximal inhibitory concentration (IC50) of paclitaxel after silencing the expression of HIF1A-AS2 and AK124454 in TNBC cells was more than double that of a negative control group, indicating that the two genes can lead to paclitaxel resistance in TNBC cells. They also established a resistance prediction model based on these two genes, which can help TNBC patients develop personalized treatment plans. Cancer stem cells are located in the cancer cell mass, which is the “culprit” of cancer recurrence and metastasis. Shin et al. (2019) tested the serum of 192 normal people and 179 patients with breast cancer by reverse transcription-quantitative PCR (RT-qPCR) and found that the expression of NEAT1 differed significantly. Its expression in the serum of TNBC patients was higher than that of patients with other cancer subtypes. Furthermore, in vitro and in vivo experiments have confirmed that knocking out NEAT1 can make TNBC cells sensitive to chemotherapy, indicating its involvement in chemotherapy resistance. In contrast, the lncRNAs TUSC7, taurine upregulated gene 1 (TUG1), and growth stasis-specific transcript 5 (GAS5) increase chemosensitivity, which can enhance the apoptosis effect of chemotherapy drugs on TNBC cells. The above genes are lowly expressed in TNBC drug-resistant cells, and upregulation of specific lncRNA expression can reverse chemotherapy resistance (Tang TL et al., 2018; Zheng SP et al., 2020; Zheng BH et al., 2021) (Table 6, Fig. 3).
    transl

    Table 6  LncRNAs associated with TNBC chemotherapy resistance
    LncRNAChangeMechanismOutcomeCellsMethodReference
    OTUD6B-AS1 Up OTUD6B-AS1/miR-26a-5p/MTDH axis PTX resistance 231 and HCC1937 qRT-PCR, CCK-8, calcein AM/PI-staining assay, Transwell assay, etc. Li et al., 2021
    H19 Up AKT signal pathway PTX resistance Hs578Bst, MCF-10A, TNBC cell lines (453, 157, and 231) qRT-PCR, MTT assay, Annexin V/PI, WB, etc. Han et al., 2018
    HIF1A-AS2, AK124454 Up Unknown PTX resistance 231, BT549, Hs578T, and 293T qRT-PCR, CCK-8, Transwell assay, and microarray data Jiang et al., 2016
    NEAT1 Up Increase tumor stem cells CIS and PTX resistance 231 qRT-PCR, MTT assay, Annexin V/PI, ALDH assay, etc. Shin et al., 2019
    TUSC7 Down Bind withmiR-1224-3p PTX and carboplatin resistance 468 RT-qPCR, CCK-8, etc. Zheng et al., 2021
    TUG1 Down TUG1/miR-197/NLK axis CIS resistance MCF-10A, 231, and BT549 qRT-PCR, CCK-8, dual luciferase reporter assay, etc. Tang TL et al., 2018
    GAS5 Down GAS5/miR-378a-5p/SUFU axis CIS and PTX resistance 231 and BT549 RT-qPCR, dual luciferase reporter gene, Annexin V/PI, etc. Zheng SP et al., 2020

    LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; OTUD6B-AS1: ovarian tumor domain-containing 6B-antisense RNA 1; HIF1A-AS2: hypoxia-inducible factor 1α‍-antisense RNA 2; NEAT1: nuclear paraspeckle assembly transcript 1; TUSC7: tumor suppressor candidate 7; TUG1: taurine upregulated gene 1; GAS5: growth stasis-specific transcript 5; miR: microRNA; MTDH: metadherin; AKT: protein kinase B; NLK: nemo-like kinase; SUFU: suppressor of fused homolog; PTX: paclitaxel; CIS: cisplatin; 231: MDA-MB-231; 453: MDA-MB-453; 157: MDA-MB-157; 468: MDA-MB-468; qRT-PCR: quantitative real-time polymerase chain reaction (PCR); RT-qPCR: reverse transcription-quantitative PCR; CCK-8: cell counting kit‐8; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PI: propidium iodide; WB: western blotting; ALDH: aldehyde dehydrogenase.

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    fig

    Fig. 3  Diagram of the mechanisms of action of lncRNAs associated with TNBC chemotherapy resistance. LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; OTUD6B-AS1: ovarian tumor domain-containing 6B-antisense RNA 1; miR: microRNA; MTDH: metadherin; AKT: protein kinase B; NEAT1: nuclear paraspeckle assembly transcript 1; TUSC7: tumor suppressor candidate 7.

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    Studies on the relationship between lncRNA and drug resistance are increasing, and the outcomes of these studies show that lncRNAs play an important role (

    Singh et al., 2023). Some lncRNAs appear resistant to paclitaxel, while others are resistant to cisplatin. We hypothesize that lncRNAs could be used in the clinic to treat TNBC-resistant patients based on their ability to reverse drug resistance by regulating lncRNA expression in cellular experiments, but the idea is still in its infancy and further research is needed.
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    6 Summary of lncRNA regulatory mechanisms

    LncRNA regulates the malignant behavior of TNBC cells through various complex mechanisms, including the following four main categories. Firstly, lncRNA can bind to proteins to regulate cell behavior. For example, lncRNA T376626 can bind to laminin γ2 (LAMC2) protein to regulate TNBC proliferation, migration, and invasion (

    He et al., 2023). Secondly, lncRNA can regulate the transcription or translation of downstream genes. For example, signal transducer and activator of transcription 3 (STAT3) is a gene that can promote the occurrence of breast cancer and accelerate the proliferation, metastasis, and chemotherapy resistance of tumor cells, while ZFAS1 can promote the occurrence and development of TNBC by increasing the expression of the STAT3 protein (Sharma et al., 2021). Similarly, lncRNA PTCSC3 can reduce the expression of the lncRNA H19 gene and inhibit the proliferation of TNBC cells (Wang N et al., 2019). Thirdly, lncRNA can also serve as a molecular blocker that binds to related molecules downstream and exerts biological effects by regulating related signaling pathways. For example, DANCR can bind to the RXRA gene, thereby activating the PI3K/AKT signaling pathway and promoting the proliferation and invasion of TNBC cells (Tang JM et al., 2018). Finally, competing endogenous RNA (ceRNA) is a mechanism by which lncRNA can competitively bind miRNA with target genes (Liu et al., 2014) and is the mechanism of action of most of the above lncRNAs. They can act as ceRNA to combine with miRNAs to regulate the expression of target genes in TNBC cells and exert biological effects. For example, lncRNA WEE2-AS1 can bind to miR-32-5p, release the inhibition of TOB1 by miR-32-5p, and promote the proliferation, invasion, and migration of TNBC cells (Wang et al., 2020). Besides, lncRNA ASMTL-AS1 can bind miR-1228-3p competitively with SOX17, thereby regulating the expression of the target gene SOX17 and inhibiting the growth and proliferation of TNBC cells (Sun J et al., 2021). Also, lncRNAs ZNF469-3, LncMIR503HG, WEE2-AS1, CARMN, and OTUD6B-AS1 all play roles in TNBC invasion, proliferation, migration, and chemoresistance through ceRNA mechanisms (Wang PS et al., 2018; Fu J et al., 2019; Wang R et al., 2020; Li et al., 2021; Sheng et al., 2021). Nevertheless, some studies have shown that ceRNA profiles in breast cancer tissues differ from those of matched normal tissues. For example, several ceRNAs are active in cancer but not in normal cells, and vice versa (Paci et al., 2014). The use of the mechanism for the treatment of TNBC patients remains to be further explored (Fig. 4).
    transl

    fig

    Fig. 4  Diagram of the pattern of lncRNA regulatory mechanisms in TNBC cells. 1: LncRNA binds to proteins; 2: LncRNA regulates downstream gene transcription or translation; 3: LncRNA regulates downstream-related signaling pathways; 4: The ceRNA mechanism of lncRNA and mRNA co-competing to bind miRNA. LncRNA: long non-coding RNA; TNBC: triple-negative breast cancer; mRNA: messenger RNA; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; NF-κB: nuclear factor-κB; miRNA: microRNA; ceRNA: competing endogenous RNA.

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    7 Universal effects of lncRNAs

    The lncRNAs exemplified above play an important role not only in the development of TNBC but also in other types of breast cancer, and even other types of cancer. For example,

    Swellam et al. (2021) found that NEAT1 is highly expressed in TNBC tissue or serum, and this can be used as a marker for the diagnosis of TNBC. However, Knutsen et al. (2022) found that NEAT1 is highly expressed not only in TNBC subtypes, but also in Her-2 positive and luminal B breast cancer subtypes. In addition, signal pathways such as PI3K/AKT and MAPK are found in most cellular metabolic processes, and lncRNAs that can affect these signaling pathways can regulate the occurrence and development of various cancers. For example, DANCR can regulate the proliferation and invasion of TNBC cells by influencing the PI3K/AKT signaling pathway, which also plays a crucial role in regulating cell proliferation and invasion in prostate cancer cells (Tang JM et al., 2018; Sun WD et al., 2021). The diagnostic lncRNAs ZFAS1, XIST, and NEAT1 have also been reported in recent years to be highly expressed in pancreatic, cervical, and colon cancers, with the potential to promote the development of cancer cells (Zhang M et al., 2018; Zhu et al., 2018; Feng et al., 2019; Yang et al., 2020; Ghafouri-Fard et al., 2021; Lu et al., 2021; Rao et al., 2021; Shao et al., 2021). Therefore, finding a gene with TNBC specificity is not easy, and combining it with the patient’s medical history or imaging examination may increase the accuracy of auxiliary judgment. Secondly, accuracy could also be increased by combining multiple genes, such as lncRNAs TUSC7 and NF-‍κB. This pathway has a role only in TNBC cells, and combining these two variables could provide more accurate information relevant to TNBC.
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    8 Immunotherapy of lncRNAs

    Immunotherapy is a new treatment method. The normal immune system of the body can distinguish between its own cells and foreign cells through immune checkpoints, thereby preventing immune damage to its own healthy cells. Tumor cells can use immune checkpoints to evade killing (

    Jiang, 2014). Programmed cell death-1 (PD-1) is an immune checkpoint protein expressed on T lymphocytes that binds to programmed cell death-ligand 1 (PD-L1) on the surface of tumor cells, leading to T lymphocyte apoptosis, and plays an important role in tumor immune escape. Regulating the expression of PD-1/PD-L1 has become a current research hotspot (Wan et al., 2022). The KEYNOTE-522 trial has moved the PD-1 inhibitor Pabolizumab from advanced treatment of TNBC to early treatment and has achieved a good therapeutic effect (Mittendorf et al., 2020). The XIST mentioned above not only has a role in diagnosing TNBC and predicting its prognosis, but also is involved in the tumor immune escape mechanism (Samir et al., 2021). XIST can promote the occurrence and development of TNBC cells by affecting PD-L1. Moreover, LINK-A did not only lead to the progression of TNBC through HIF-1α. Hu et al. (2019) analyzed the potential relationship between LINK-A and the immune microenvironment through TCGA and found that human breast cancer tissue with high expression of LINK-A showed low CD8+CD3+ lymphocyte infiltration. They also measured the infiltration of CD8+ T cells in TNBC patients after pembrolizumab (anti-PD-1) treatment and found that CD8+ T cell infiltration was negatively correlated with LINK-A expression. The above results indicate that LINK-A plays an important role in the immune regulatory mechanism of TNBC (Hu et al., 2019). LncRNA regulates the occurrence and development of TNBC via the immune mechanism and can serve as a new target for TNBC immunotherapy.
    transl

    At present, immunotherapy with lncRNA is still in its early stages and more, larger, multicenter studies are required.

    transl

    9 Discussion

    Treatment options for TNBC are limited due to the lack of effective therapeutic targets. Epigenetics refers to heritable changes in gene function that occur without sequence changes in DNA. These mechanisms include covalent modification of DNA and protein, chromatin remodeling, and regulation of ncRNA. They control biological phenotypes through regulating gene expression. Epigenetic modification abnormalities exist in a variety of cancers. Therefore, it is very important to explore the following issues related to the occurrence and development of TNBC: (1) Whether the epigenetic decorator pattern changes the expression of some genes; (2) Which dimension of epigenetics has changed; (3) How changes in gene expression and protein function cause changes in the pathological level of TNBC. Only by answering these questions can we understand the pathogenesis of TNBC more thoroughly and propose more targeted prevention, diagnosis, and treatment plans.

    transl

    As an important dimension in epigenetics, lncRNA is an obvious object of study in basic TNBC research (

    Herman et al., 2022). There are two main ways by which lncRNA regulates the level of epigenetic modification. On the one hand, lncRNA can directly affect the methylation of DNA and RNA. For example, miR-26b is a tumor suppressor gene in breast cancer. Long et al. (2020) showed that TatD DNase domain-containing 1 (TATDN1) has a positive regulatory effect on the methylation of the miR-26b gene through methylation-specific PCR, and promotes the proliferation and invasion of TNBC cells by reducing the expression of miR-26b. Similarly, the methylation of MALAT1 can promote high expression of B-cell CLL/lymphoma 11A (BCL11A) DNA methyltransferase 1 (DNMT1) by inhibiting the miR-137/BCL11A pathway, thereby inhibiting tumor development (Hu et al., 2023). On the other hand, lncRNA can affect protein modification to exert biological effects. For example, DANCR binds with RXRA and increases its serine 49/78 phosphorylation via GSK3β, resulting in activation of PIK3CA transcription, and subsequently enhances PI3K/AKT signaling and TNBC tumorigenesis (Tang JM et al., 2018).
    transl

    Liquid biopsy refers to the examination of a patient’s body fluid. By detecting the marker information released by tumor cells into the body fluid, we can obtain comprehensive information regarding oncogene or protein expression in the patient’s body. This has the advantages of convenient material selection, minimal trauma, and high accuracy, and can yield results consistent with histology. For example,

    Liu et al. (2017) performed RT-qPCR detection of lncRNAs ANRIL, HIF1A-AS2, and UCA1 in the plasma and tumor tissues of enrolled patients, and found that the expression levels of these three genes in TNBC serum and tumor tissues were higher than those in NTNBC. Manoochehri et al. (2023) obtained similar results from examination of TNBC and normal breast tissue, peripheral blood of TNBC cases and controls, and TNBC cells. The above results indicate that the results of liquid biopsy are consistent with the histological results.
    transl

    In this study, we found that some lncRNAs have value both in the diagnosis of TNBC and in assessing prognosis. For example, the detection of NEAT1 in serum enables early diagnosis of TNBC patients, and the prognosis of patients can be measured by the level of expression of this gene. Similarly, ZFAS1 can be used not only as a diagnostic marker for TNBC patients, but also to predict the proliferative capacity of tumor cells and patient prognosis by the level of expression. LncRNA is involved in various aspects of the physiological mechanisms of TNBC cells and plays a wide-ranging role. Therapeutic regimens targeting lncRNA may offer a ray of hope for TNBC patients, but reproducible biological targets are still extremely scarce in TNBC and more studies with larger sample sizes and stronger evidence are warranted. In addition, ceRNA is the mechanism of action of most lncRNAs and the network is interconnected and complicated. How to find the key nodes against ceRNA oncogenic mechanisms is very important, otherwise treatment may lead to failure and even secondary tumor occurrence. Thus, caution is needed (

    Giza et al., 2014; Kotterman and Schaffer, 2014; Nitzan et al., 2014). LncRNA is also involved in regulating various metabolic pathways in cells. In the future, we can explore whether lncRNA in TNBC regulates specific metabolic pathways from the perspective of metabolomics analysis, thereby finding new target biomarker sites (Zhu et al., 2022). In addition, lncRNA often interacts with miRNA to jointly regulate important physiological and pathological processes in the development of TNBC, so we speculate that the two could be combined to determine the prognosis of patients (Liu AN et al., 2019; Youness et al., 2019). With the deepening understanding of TNBC, it has been found that there are also many different subtypes of TNBC. In the future, it may be possible to pinpoint which specific lncRNA plays oncogenic roles in specific TNBC subtypes so that more precise individualized treatments can be developed. We can also measure the cancer risk of patients by combining the expression of lncRNA with their clinical characteristics, and develop a medical algorithm that relies on risk sharing to make the prediction results more reliable.
    transl

    10 Conclusions

    In this review, we discussed and summarized the roles of lncRNAs in the diagnosis, prognosis, and drug resistance of TNBC, and found that they play an important role in the development of TNBC. We can determine the condition of TNBC by detecting the expression levels of related lncRNAs in the patient’s serum, and even combine this with downstream miRNAs or proteins to improve accuracy. In addition, these genes have the potential to become new therapeutic targets for TNBC.

    transl

    Contributions Statement

    Qiuhui YANG: writing – original draft, conceptualization, and formal analysis. Yeqin FU: investigation and writing – review & editing. Jiaxuan WANG: software and visualization. Hongjian YANG: conceptualization, supervision, and writing – review & editing. Xiping ZHANG: conceptualization, funding acquisition, supervision, and writing – review & editing. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.

    Acknowledgements

    This work was supported by the Zhejiang Provincial Natural Science Foundation of China (No. LBY21H160001).

    Compliance with ethics guidelines

    Qiuhui YANG, Yeqin FU, Jiaxuan WANG, Hongjian YANG, and Xiping ZHANG declare that they have no conflict of interest.

    This article does not contain any studies with human or animal subjects performed by any of the authors.

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