lncRNA and breast cancer: Progress from identifying mechanisms to challenges and opportunities of clinical treatment

Abstract

Breast cancer is a malignant tumor that has a high mortality rate and mostly occurs in women. Although significant progress has been made in the implementation of personalized treatment strategies for molecular subtypes in breast cancer, the therapeutic response is often not satisfactory. Studies have reported that long non-coding RNAs (lncRNAs) are abnormally expressed in breast cancer and closely related to the occurrence and development of breast cancer. In addition, the high tissue and cell-type specificity makes lncRNAs particularly attractive as diagnostic biomarkers, prognostic factors, and specific therapeutic targets. Therefore, an in-depth understanding of the regulatory mechanisms of lncRNAs in breast cancer is essential for developing new treatment strategies. In this review, we systematically elucidate the general characteristics, potential mechanisms, and targeted therapy of lncRNAs and discuss the emerging functions of lncRNAs in breast cancer. Additionally, we also highlight the advantages and challenges of using lncRNAs as biomarkers for diagnosis or therapeutic targets for drug resistance in breast cancer and present future perspectives in clinical practice.

Keywords: breast cancer; drug resistance; immunosuppression; invasion; lncRNA; metastasis; proliferation.

Graphical abstract

Figure 1

The classification of lncRNAs based on their genomic position, subcellular localization lncRNAs are divided into six types: (1) enhancer lncRNAs; (2) intron lncRNA; (3) antisense lncRNA; (4) sense lncRNA; (5) intergenic lncRNA; (6) bidirectional lncRNA.

Figure 2

The functions of lncRNAs (A) lncRNAs are translated into polypeptides to regulate gene expression, such as LINC00908 and LINC00665. (B) lncRNA NORAD binds to transcription factors in the nucleus to keep it away from chromatin to-inhibiting gene transcription, whereas lncRNA HOTAIR combines with transcription factors to promote gene transcription. (C) lncRNAs combine with the corresponding promoter region to form an R loop to increase transcription activity and DNA methylation, such as lncRNA Khps1 and TARID. (D) lncRNAs interfere with mRNA splicing and form different splicing forms, such as lncRNA LASTR, MALAT1, and SRSP. (E) lncRNA as a molecular decoy (NORAD) recruits proteins (1/2-sbsRNAs) or binds miRNA (lnc00899) to regulate mRNA stability. (F) lncRNAs interact with translation-related proteins to participate in the translation process of mRNA, such as lincRNA-p21, ROR, and AFAP1-AS1. (G) lncRNA NDRG1-OT1 and ANCR recruit different proteins to affect protein stability. (H) lncRNA BLAT1, BCLIN25, and H19 are involved in the DNA methylation process. In addition, lncRNA HOTAIR is closely related to histone modification. (I) Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from TAMs regulates aerobic glycolysis of breast cancer cells.

Figure 3

lncRNAs modulate the proliferation, metastasis, and apoptosis of breast cancer cells (A) lncRNA regulates cell proliferation by activating or inhibiting specific signaling pathways in breast cancer. (B) lncRNAs can regulate the expression of mesenchymal markers vimentin, fibronectin, N-cadherin, Twist1, ZEB1, and epithelial cell junction proteins E-cadherin, claudins, and α-catenin to affect tumor cell metastasis. lncRNA also regulates the stemness of CSCs to obtain metastatic ability. (C) lncRNA mainly affects tumor cell apoptosis through p53 and caspase signal transduction pathways. MALAT1 and PICART1 participate in the process of cell apoptosis by regulating the activity of p53, and APOC1P1-3 and LINC00628 promote cell apoptosis through the expression of caspase-3, Bax, and Bcl-2.

Figure 4

lncRNA affects drug resistance in breast cancer cells (A) lncRNAs participate in endocrine therapy resistance: lncRNA H19 increases endocrine therapy resistance by promoting autophagy and ERα expression. lncRNA TMPO-AS1 stabilizes the mRNA of ERα-encoding gene ESR1, leading to endocrine resistance. In addition, ROR promotes the degradation of ERK-specific phosphatase DUSP1, thereby enhancing ERK phosphorylation, activating ER signal transduction independent of estrogen, leading to intrinsic resistance to endocrine therapy. Furthermore, UCA1 confers tamoxifen resistance by regulating the EZH2/p21 axis. In contrast, GAS5 negatively regulates endocrine therapy resistance through PTEN/AKT/mTOR signaling. (B) lncRNAs participate in HER2-targeted therapy: lncRNA AFAP1-AS1 promotes the translation of HER2 by binding to AUF1 or is packaged into exosomes, acting on recipient cells to promote resistance to HER2-targeted therapy. AGAP2-AS1 increases H3K27 acetylation in the MyD88 promoter region and activates the NF-κB signaling pathway to resist HER2-targeted therapy. In addition, SNHG14 can inhibit trastuzumab-induced apoptosis by upregulating Bcl2. (C) lncRNAs in breast cancer chemoresistance: the activation of NF-κB mediated by lncRNA BORG can inhibit chemotherapy-induced DNA damage. lncRNA can affect the cell cycle by regulating the cycle-related proteins in breast cancer to participate in chemotherapy resistance, for example, LINC00511, HIF1A-AS2, and AK124454. PTENP1 and LINC00968 regulate breast cancer chemotherapy resistance by activating PIK/AKT and WNT/catenin, respectively. (D) lncRNAs are involved in immunosuppression: LINK-A caused cAMP and PKA-mediated reduction of TRIM71 phosphorylation. The reduction of TRIM71 phosphorylation will enhance the degradation of PLC, leading to downregulation of antigenicity. lncRNA SNHG1 regulates the differentiation of Tregs by regulating the expression of IDO, thereby affecting the immune escape of breast cancer. lncRNA INCR1 regulates tumor interferon signaling. The main transcript of INCR1 binds to HNRNPH1 to block its inhibitory effect on neighboring genes PD-L1 and JAK2, thereby promoting the expression of PD-L1 and JAK2.