The Mechanisms of lncRNA-Mediated Multidrug Resistance and the Clinical Application Prospects of lncRNAs in Breast Cancer

Abstract

Breast cancer (BC) is a highly heterogeneous disease and presents a great threat to female health worldwide. Chemotherapy is one of the predominant strategies for the treatment of BC; however, multidrug resistance (MDR) has seriously affected or hindered the effect of chemotherapy. Recently, a growing number of studies have indicated that lncRNAs play vital and varied roles in BC chemoresistance, including apoptosis, autophagy, DNA repair, cell cycle, drug efflux, epithelial-mesenchymal transition (EMT), epigenetic modification and the tumor microenvironment (TME). Although thousands of lncRNAs have been implicated in the chemoresistance of BC, a systematic review of their regulatory mechanisms remains to be performed. In this review, we systematically summarized the mechanisms of MDR and the functions of lncRNAs mediated in the chemoresistance of BC from the latest literature. These findings significantly enhance the current understanding of lncRNAs and suggest that they may be promising prognostic biomarkers for BC patients receiving chemotherapy, as well as therapeutic targets to prevent or reverse chemoresistance.

Keywords: MDR; breast cancer; chemoresistance; chemotherapy; exosome; lncRNA.

Figure 1

Overview of the relationship between lncRNAs and chemoresistance in this review.

Figure 2

Models of lncRNA mechanisms of action. (a) lncRNAs may act as decoys to lead transcription factors (TFs) away from DNA targets or directly bind to sequester complementary RNA transcripts, such as miRNAs (also known as competing endogenous RNAs or “sponges” of miRNAs). The effect of this biological function is to regulate the expression of the genes and the translation of the mRNA. (b) lncRNAs may act as scaffolds to assemble two or more proteins into a complex. (c) lncRNAs may act as guides to regulate gene expression by recruiting proteins, such as chromatin modification enzymes. (d) lncRNAs may act as enhancers in chromosome looping (also known as cis-regulatory elements) [23].

Figure 3

Overview of the apoptosis pathways (lncRNA H19 is used as example clarifying the mechanism). The intrinsic pathway of apoptosis is initiated by the cell itself in response to cytotoxic stimuli. The extrinsic pathway is initiated via death receptors stimulated by death ligands. When caspase 3 is activated, the two pathways merge and lead to cell death [37]. Bax channels, Bcl-2-associated protein X channels; Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma extra-large; Mcl-1 induced myeloid leukemia cell differentiation protein 1; DISC, death inducing signalling complex.

Figure 4

Summary of the steps involved in autophagy (lncRNA H19 and ROR are used as examples for clarifying the mechanism). Autophagy is initiated by the stepwise engulfment of cellular materials by the phagophore, which sequesters materials in double-membraned vesicles known as autophagosomes [75]: (a) When mammalian target of rapamycin (mTOR) is inhibited, mTOR complex 1 (mTORC1) isolates from the ULK1 complex. The first step of vesicle nucleation is activating Vps34, a class III phosphatidylinositol 3-kinase (PI3K), to produce phosphatidylinositol-3-phosphate (PtdIns3P). (b) A part of the vesicle elongation process is to bind phosphatidylethanolamine (PE) to LC3. (c) The formation of autophagosomes is completed after closure of the phagophore double membrane, and then autophagosomes fuse with lysosomes, resulting in degradation of the contents.

Figure 5

Cell cycle progression and CDKs (LINC00511 is used as example for clarifying the mechanism). The cell cycle is divided into four distinct phases: G1 (postmitotic interphase), S phase (DNA synthesis phase), G2 (postsynthetic phase), and M phase (mitosis). Mitogenic signals activate CDK4 and CDK6 complexes to initiate the phosphorylation (P) of key substrates, including the tumor suppressor retinoblastoma protein (RB), thereby releasing a gene expression program that is coordinated by the E2F family of transcription factors. The subsequent activation of CDK2-Cyclin A and CDK2-Cyclin E complexes initiates DNA replication. With the completion of DNA replication, CDK1–Cyclin A and CDK1–Cyclin B complexes form to phosphorylate targets in G2 phase. In the absence of DNA damage and following proper preparation for chromosomal segregation, the cellular default is to activate CDK1–Cyclin B complexes and progress into mitosis [98]. CDK, cyclin-dependent Ser/Thr kinase.

Figure 6

Scheme of the proposed mechanism related to lncRNA SNHG7 in EMT process. SNHG7, as a molecular sponge of miR-34a, mediating EMT process, which is driven by EMT-transcription factors (SLUG, SNAIL1, TWIST1/2, ZEB1/2) that repress epithelial marker genes and activate mesenchymal marker genes. EMT, Epithelial–mesenchymal transition; SNHG7, small nucleolar RNA host gene 7.

Figure 7

Scheme of the proposed mechanism related to Linc00969 in trastuzumab-resistant breast cells. Linc00969 induces trastuzumab resistance by binding to the HUR protein and promoting the translation of ERBB2 mRNA. In addition, extracellular Linc00969 from trastuzumab-resistant cells was packaged into exosomes and disseminated trastuzumab resistance in trastuzumab-sensitive cells [137]. ILVs, intraluminal vesicles; MVBs, multivesicular bodies; HUR, Hu antigen R.

Figure 8

Brief sketch map of our conclusions in this review: (a) A certain lncRNA regulates chemoresistance in a subtype of BC cell via various signaling pathways; (b) a certain lncRNA induces different subtypes of BC cells to resist chemotherapeutic agents via the same signaling pathway; (c) a certain subtype of BC cell is regulated by various lncRNAs via the same signaling pathway; (d) the lncRNAs UCA1, ROR, and GAS5 are used as examples to provide a further detailed explanation.