Correction: Ye et al. The Mechanisms of lncRNA-Mediated Multidrug Resistance and the Clinical Application Prospects of lncRNAs in Breast Cancer. Cancers 2022, 14, 2101

Abstract

Figures

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.

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.

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.

Tables

Table 1. The role of lncRNAs in regulating cell survival and death in chemoresistant breast cancers.

Function	LncRNA	Type	Genomic Location	Expression Level *	Resistant Drugs	Cell Lines	Possible Mechanism §	References
Suppressing apoptosis	GAS5	Tumor suppressor	chr1q25.1	↓	paclitaxel; cisplatin	MDA-MB-231; BT549	↑ miR-378a-5p/↓ SUFU signaling	[49]
	MEG3	Tumor suppressor	chr14q32	↓	doxorubicin; paclitaxel	Hs578T; MCF-7; MDA-MB-231	↑ TGF-β and N-cadherin protein; ↓ MMP 2, ZEB 1 and COL3A1 expression; ↓ miR-4513/↑ PBLD axis	[50,51]
	PTENP1	Tumor suppressor	N/A °	↓	adriamycin	MDA-MB-231; T-47D; MCF-7	↑ miR-20a/↓ PTEN axis; ↑ PI3K/AKT pathway	[52]
	UCA1	Oncogene	chr19q13.12	↑	tamoxifen	MCF-7; T-47D; LCC2; LCC9	↑ EZH2/↓ p21 axis; ↑ PI3K/AKT pathway; ↑ mTOR pathway	[53,54]
	H19	Oncogene	chr11p15.5	↑	paclitaxel	MDA-MB-453; MDA-MB-157; MDA-MB-231; ZR-75-1; MCF-7	↑ AKT pathway; ↓ BIK; ↓ NOXA	[47,48]
	PRLB	Oncogene	chr8p11.21	↑	5-fluorouracil	MDA-MB-231	↓ miR-4766-5p/↑ SIRT1 axis	[55]
	LINP1	Oncogene	chr10	↑	doxorubicin;5-fluorouracil	MDA-MB-231; MDA-MB-468; MCF-7	↓ p53; ↓ E-cadherin; ↑ N-cadherin; ↑ vimentin; ↓ caspase9/Bax	[56]
	LOC645166	Oncogene	N/A	↑	adriamycin	MDA-MB-231; MCF-7	↑ NF-κB/GATA3 axis	[57]
Autophagy	EGOT	Tumor suppressor	N/A	↓	paclitaxel	MCF-7; T-47D; UACC-812; SK-BR-3; HCC70; MDA-MB-453; MDA-MB-231; MDA-MB-468; BT549; Hs578T	↑ ITPR1	[58]
	ROR	Oncogene	chr18q21.31	↑	tamoxifen	BT474	↑ MDR1 and GST-π mRNA; ↓ LC3 and Beclin 1	[59]
	H19	Oncogene	chr11p15.5	↑	tamoxifen	MCF-7	H19/SAHH/DNMT3B axis; ↑ Beclin1	[60]
	ZNF649-AS1	Oncogene	chr19q13.41	↑	trastuzumab	SK-BR-3; BT474	↑ ATG5 through associating with PTBP1	[61]
	ASAH2B-2	Oncogene	N/A	↑	everolimus	BT474; MCF-7	↑ mTOR pathway	[62]
DNA repair	HCP5	Oncogene	N/A	↑	cisplatin	MDA-MB-231	↓ PTEN	[63]
	PTENP1	Tumor suppressor	N/A	↓	adriamycin	MDA-MB-231; T-47D; MCF-7	↑ miR-20a/↓ PTEN axis; ↑ PI3K/AKT pathway	[52]
	GAS5	Tumor suppressor	chr1q25.1	↓	tamoxifen	MCF-7	↑ AKT/mTOR pathway; ↓ PTEN	[64]
	UCA1	Oncogene	chr19q13.12	↑	trastuzumab	SKBR-3	↓ miR-18a/↑ Yes-associated protein 1 (YAP1); ↓ PTEN; ↑ CD6	[65]
	UCA1	Oncogene	chr19q13.12	↑	paclitaxel	MCF-7	↓ miR-613/↑ CDK12 axis	[66]
	GAS5	Tumor suppressor	chr1q25.1	↓	trastuzumab; lapatinib	SKBR-3	↑ miR-21; ↓ PTEN; ↑ mTOR; ↑ Ki-67	[67]
	LINC-PINT	Tumor suppressor	N/A	↓	paclitaxel	MDA-MB-231; BT-20	↑ NONO	[68]
	H19	Oncogene	chr11p15.5	↑	doxorubicin	MCF-7	↓ PARP1	[69]
	lncMat2B	Oncogene	N/A	↑	cisplatin	MDA-MB-231; MCF-7	N/A	[70]
	ADAMTS9-AS2	Tumor suppressor	N/A	↓	tamoxifen	MCF-7	↑ microRNA-130a-5p; ↓ PTEN	[71]

Table 2. The function of lncRNAs in chemoresistant breast cancers, including regulating cell cycle, drug efflux metabolism, EMT, and epigenetic alteration.

Function	LncRNA	Type	Genomic Location	Expression Level *	Resistant Drugs	Cell Lines	Possible Mechanism §	References
regulating cell cycle	TMPO-AS1	Oncogene	N/A °	↑	tamoxifen	MCF-7	stabilize ESR1 mRNA	[109]
	CASC2	Oncogene	N/A	↑	paclitaxel	MDA-MB-231; MCF-7	↓ miR-18a-5p/↑ CDK19 axis	[110]
	LINC00511	Oncogene	chr17q24.3	↑	paclitaxel	MDA-MB-231; MCF-7; T-47D; Hs-578T	↓ miR-29c/↑ CDK6 axis	[104]
	NEAT1	Oncogene	N/A	↑	cisplatin/taxol	MDA-MB-231	N/A	[111]
	LOL	Oncogene	N/A	↑	tamoxifen	MCF-7	↓ let-7 miRNA; ↓ ERα signaling	[112]
	UCA1	Oncogene	chr19q13.12	↑	tamoxifen	MCF-7; T-47D; LCC2; LCC9; BT474	↑ EZH2/↓ p21 axis; ↑ PI3K/AKT pathway; ↓ miR-18a/↑ HIF1α	[54,113]
	DSCAM-AS1	Oncogene	chr21q22.3	↑	tamoxifen	MCF-7; T-47D; SK-BR-3; MDA-MB-231	↑ epidermal growth factor receptor pathway substrate 8 (EPS8); ↑ ESR1; ↑ ERα; ↓ miR-137	[114,115]
	FTH1P3	Oncogene	N/A	↑	paclitaxel	MCF-7; MDA-MB-231; MDA-MB-468; MDA-MB-453	↓ miR-206/↑ ABCB1	[116]
	MAFG-AS1	Oncogene	N/A	↑	tamoxifen	MCF-7; BT474; T-47D; MCF10A	↓ miR-339-5p/↑ CDK2 axis	[117]
	PRLB	Oncogene	chr8p11.21	↑	5-fluorouracil	MDA-MB-231	↓ miR-4766-5p/↑ SIRT1 axis	[55]
	UCA1	Oncogene	chr19q13.12	↑	trastuzumab	SKBR-3	↓ miR-18a/↑ Yes-associated protein 1 (YAP1); ↓ PTEN; ↑ CD6	[65]
	LINP1	Oncogene	chr10	↑	doxorubicin; 5-fluorouracil	MDA-MB-231; MDA-MB-468; MCF-7	↓ p53; ↓ E-cadherin; ↑ N-cadherin; ↑ vimentin; ↓ caspase9/Bax	[56]
	TROJAN	Oncogene	N/A	↑	palbociclib	MCF7; T47D	↑ NKRF/CDK2 axis	[5]
	DILA1	Oncogene	N/A	↑	tamoxifen	MCF-7; 293-T; T47D	↑ Cyclin D1	[4]
	ARA	Oncogene	Xq23	↑	adriamycin	MCF-7	multiple signaling pathways	[118]
drug efflux metabolism	GAS5	Tumor suppressor	chr1q25.1	↓	adriamycin	MCF-7	↑ miR-221-3p/↑ Dickkopf 2 (DKK2) axis; ↑ Wnt/b-catenin pathway	[119]
	BC032585	Tumor suppressor	chr9	↓	taxane; anthracyclines	MDA-MB-231	↑ MDR1	[120]
	Linc00518	Oncogene	chr6	↑	multidrugadriamycin; vincristine; paclitaxel	MCF-7	↓ miR-199a/↑ MRP1 axis	[121]
	FTH1P3	Oncogene	N/A	↑	paclitaxel	MCF-7; MDA-MB-231; MDA-MB-468; MDA-MB-453	↓ miR-206/↑ ABCB1	[116]
	ROR	Oncogene	chr18q21.31	↑	tamoxifen	BT474	↑ MDR1 and GST-π mRNA; ↓ LC3 and Beclin 1	[59]
	H19	Oncogene	chr11p15.5	↑	doxorubicin; anthracyclines	MCF-7	↑ CUL4A-ABCB1/MDR1 pathway	[122]
	RP11-770J1.3 TMEM25	Oncogene	N/A	↑	paclitaxel	MCF-7	↑ MRP, BCRP and MDR1/P-gp	[123]
EMT	LINP1	Oncogene	chr10	↑	tamoxifen	MCF-7; T-47D	↓ ER expression signaling pathway	[124]
	MEG3	Tumor suppressor	chr14q32	↓	doxorubicin	Hs578T	↑ TGF-β and N-cadherin protein; ↓ MMP 2, ZEB 1 and COL3A1 expression	[50]
	NONHSAT101069	Oncogene	chr5	↑	epirubicin	MCF-7	↓ miR-129-5p/↑ Twist1 axis	[125]
	NEAT1	Oncogene	N/A	↑	cisplatin/taxol	MDA-MB-231	N/A	[111]
	H19	Oncogene	chr11p15.5	↑	tamoxifen; paclitaxel	SK-BR-3; MCF-7	↑ Wnt pathway; ↓ miR-340-3p/YWHAZ axis	[126,127]
	PRLB	Oncogene	chr8p11.21	↑	5-fluorouracil	MDA-MB-231	↓ miR-4766-5p/↑ SIRT1	[55]
	LINC00894002	Tumor suppressor	X chromosome	↓	tamoxifen	MCF-7	↓ miR200/↑ TGFβ2 signaling pathway; ↑ ZEB1	[128]
	LINP1	Oncogene	chr10	↑	doxorubicin; 5-fluorouracil	MDA-MB-231; MDA-MB-468; MCF-7	↓ p53; ↓ E-cadherin; ↑ N-cadherin; ↑ vimentin; ↓ caspase9/Bax	[56]
	NEAT1	Oncogene	N/A	↑	5-fluorouracil	MCF-7; T-47D; MDA-MB-231; ZR-75-1	↓ miR-211/↑ HMGA2 axis	[129]
	ROR	Oncogene	chr18q21.31	↑	tamoxifen	MDA-MB-231; MCF-7	↓ microRNA-205; ↓ E-cadherin; ↑ vimentin; ↑ ZEB1 and ZEB2	[130]
	DLX6-AS1	Oncogene	N/A	↑	cisplatin	HCC1599; MDA-MB-231; HCC1806; Hs578T	↓ miR-199b-5p/paxillin signaling	[131]
	ROR	Oncogene	chr18q21.31	↑	5-fluorouracil; paclitaxel	T-47D; MCF-7; SK-BR-3; Bcap-37; MDA-MB-231; MCF10A	↓ E-cadherin; ↑ vimentin and N-cadherin	[132]
	ATB	Oncogene	chr14q11.2	↑	trastuzumab	SKBR-3	↓ miR-200c; ↑ TGF-β signaling; ↑ ZEB1 and ZNF-217	[133]
	SNHG7	Oncogene	chr9q34.3	↑	trastuzumab; adriamycin; paclitaxel	SKBR3; AU565; MDA-MB-231; MCF10A; MCF-7	↓ miR-186; ↓ miR-34a	[134,135]
	DCST1-AS1	Oncogene	N/A	↑	doxorubicin; paclitaxel	MDA-MB-231; BT-549; T-47D; MCF-7	↑ TGF-β/Smad signaling through ANXA1	[136]
epigenetic alteration	LINC00969	Oncogene	N/A	↑	trastuzumab	SKBR-3; BT474	↑ translation and stability of ERBB2 mRNA	[137]
	TMPO-AS1	Oncogene	N/A	↑	tamoxifen	MCF-7	stabilize ESR1 mRNA	[109]
	ZNF649-AS1	Oncogene	chr19q13.41	↑	trastuzumab	SK-BR-3; BT474	↑ ATG5 through associating with PTBP1	[61]
	MIR2052HG	Oncogene	N/A	↑	aromatase inhibitor	MDA-MB-231; CAMA-1; Au565; 293-T; MCF-7	↑ LMTK3; ↓ AKT/FOXO3-mediated ESR1 transcription; ↓ PKC/MEK/ERK/RSK1 pathway; ↓ ERα degradation	[138]
	LINC00472	Tumor suppressor	N/A	↓	tamoxifen	MCF-7; T-47D; MDA-MB-231; Hs578T	↑ phosphorylation NF-κB	[139]
	UCA1	Oncogene	chr19q13.12	↑	tamoxifen	MCF-7; T-47D; LCC2; LCC9	↑ EZH2/↓ p21 axis; ↑ PI3K/AKT pathway	[54]
	H19	Oncogene	chr11p15.5	↑	tamoxifen; fulverstrant	LCC2; LCC9; MCF-7	↑ ERα; ↑ Notch, HGF and c-MET signaling	[140]
	BORG	Oncogene	N/A	↑	doxorubicin	D2.OR; 67NR; 4T07; 4T1	↑ NF-κB signaling; ↑ RPA1	[141]
	SNHG14	Oncogene	chr15q11.2	↑	trastuzumab	SKBR-3; BT474	↑ PABPC1; ↑ Nrf2 pathway	[142]
	MAPT-AS1	Oncogene	chr17q21.31	↑	paclitaxel	MDA-MB-231; MDA-MB-468	↑ MAPT mRNA	[143]
	Linc-RoR	Oncogene	N/A	↑	tamoxifen	MCF-7	↑ MAPK/ERK signaling; ↑ ER signaling; ↓ DUSP7	[144]
	HOTAIR	Oncogene	chr12q13.13	↑	tamoxifen; TNF-a	MCF-7; T-47D	↑ ER signaling; ↑ SRC and p38MAPK kinases; ↑ EZH2	[145,146]
	H19	Oncogene	chr11p15.5	↑	paclitaxel	ZR-75-1; MCF-7	↓ BIK; ↓ NOXA	[48]
	BDNF-AS	Oncogene	chr11p14.1	↑	tamoxifen	MCF-7; T-47D; MDA-MB-231	↑ RNH1/TRIM21/mTOR	[147]
	BCAR4	Oncogene	chr16p13.13	↑	tamoxifen	ZR-75-1	↑ ERBB2/ERBB3 pathway; ↑ AKT	[148]

Table 3. The role of exosomal lncRNAs in drug resistance in breast cancers.

LncRNA	Type	Genomic Location	Expression Level *	Resistant Drugs	Cell Lines	Possible Mechanism §	Reference
LINC00969	Oncogene	N/A	↑	trastuzumab	SKBR-3; BT474	↑ translation and stability of ERBB2 mRNA	[137]
H19	Oncogene	chr11p15.5	↑	doxorubicin	MCF-7; MDA-MB-231	N/A °	[192]
HISLA	Oncogene	chr14q31.3	↑	docetaxel	MDA-MB-231; BT-474; MDA-MB-468; MCF-7	inhibit the hydroxylation and degradation of HIF-1α	[193]
AGAP2-AS1	Oncogene	chr12q14.1	↑	trastuzumab	SKBR-3; BT474	N/A	[194]
UCA1	Oncogene	chr19q13.12	↑	tamoxifen	MCF-7; LCC2	↓ cleaved caspase-3	[190]

Full text

In the original publication [1], there were several references cited that have been retracted. Corrections have been made as follows:

Reference Updates:

The authors have deleted the following retracted references (previously cited as Refs. [5,51,57,58,64,131,148,159]). The following citations have been replaced with more recent or reliable sources:

• Ref. [64] → Updated to “Jiang, Y.; Qian, T.; Li, S.; Xie, Y.; Tao, M. Metformin reverses tamoxifen resistance through the lncRNA GAS5-medicated mTOR pathway in breast cancer. Ann. Transl. Med. 2022, 10, 366”.

• Ref. [137] → Updated to “Liu, C.; Lu, C.; Yixi, L.; Hong, J.; Dong, F.; Ruan, S.; Hu, T.; Zhao, X. Exosomal Linc00969 induces trastuzumab resistance in breast cancer by increasing HER-2 protein expression and mRNA stability by binding to HUR. Breast Cancer Res. 2023, 25, 124”.

• Ref. [185] → Updated to “Yu, Z.; Tang, H.; Chen, S.; Xie, Y.; Shi, L.; Xia, S.; Jiang, M.; Li, J.; Chen, D. Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy. Drug Resist. Updates 2023, 67, 100915”.

• Ref. [186] → Updated to “Tong, Y.; Yang, L.; Yu, C.; Zhu, W.; Zhou, X.; Xiong, Y.; Wang, W.; Ji, F.; He, D.; Cao, X. Tumor-Secreted Exosomal lncRNA POU3F3 Promotes Cisplatin Resistance in ESCC by Inducing Fibroblast Differentiation into CAFs. Mol. Ther. Oncol. 2020, 18, 1–13”.

With these corrections, the order of some references has been adjusted accordingly.

Figure Revisions:

Figure 4, Figure 7 and Figure 8: Modified to reflect the latest data and ensure consistency with the updated references.

The updated figures are attached below:

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.

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.

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.

Table Revisions:

Table 1, Table 2 and Table 3: Modified to reflect the latest data and ensure consistency with the updated references.

The updated tables are attached below:

Text Revisions:

The text has been modified to reflect the latest data and ensure consistency with the updated references.

The correction has been made to Section 5.1.3. Activating DNA Repair; Section 5.3. Drug Efflux; Section 5.5. Epigenetic Modification; Section 5.6. Modifying the TME via Exosomal lncRNAs; and Section 7.1. Association of lncRNAs and Patients with BC.

The correct sections are shown below:

5.1.3. Activating DNA Repair

Considerable evidence supports that many chemotherapeutic agents exert anticancer effects by destroying the stability of genes and activating downstream DNA damage signaling pathways [78,79]. Tumor cells may activate DNA damage repair pathways to resist DNA damage and contribute to MDR [80]. Accumulating studies have reported that lncRNAs in different human cancers are related to DNA repair in MDR [81–83]. It is widely accepted that phosphatase and tensin homolog (PTEN) controls DNA repair [84,85] and exerts multiple nuclear functions [86,87]. Moreover, it also participates in the key processes of genetic transmission to promote the fidelity of DNA replication [88–90] and chromosome segregation [91–93]. Jiang et al. and Li et al. reported that lncRNA growth arrest-specific transcript 5 (GAS5) functions as a tumor suppressor in chemoresistant BC. GAS5 induced resistance to chemotherapeutic drugs by suppressing PTEN in two situations (different molecular subtypes of BCs and different drugs) [64,67]. In addition to PTEN, poly (ADP-ribose) polymerase (PARP) also participates in the DNA repair process, serving as an enzyme to repair single-stranded breaks [94]. Wang et al. reported that H19 plays a crucial role in doxorubicin-resistant BC by downregulating PARP1 [69]. In the clinic, resistance to PARP inhibitors is common. Ideally, knockdown of H19 might increase the sensitivity of BC cells to doxorubicin and PARP inhibitors. This implies that targeting lncRNAs could reverse resistance, increase the effectiveness of treatment strategies, and achieve good clinical efficacy. As shown in Table 1, although many lncRNAs participate in DNA repair via distinct pathways in the chemoresistance of BC, they are the tip of the iceberg. It is impossible to achieve clinical translation based on the currently available information. There is still a long way to go to fully clarify the relationship between lncRNAs and DNA repair.

5.3. Drug Efflux

Drug efflux is regarded as the predominant cause of MDR in human cancers. Hydrophobic chemotherapeutic drugs can be pumped out of tumor cells via the ATP-binding cassette (ABC) transporter superfamily, thereby reducing the effectiveness of the drugs and possibly resulting in tumor recurrence [149]. To date, according to their sequence homology and structural similarities, a total of 48 human ABC transporter genes have been divided into seven subfamilies (ABCA to ABCG) [150]. Among the ABC transporter superfamily, P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) are considered to be the most closely related to MDR in cancer cells [149,151]. Recently, a number of studies have shown that lncRNAs play a key role in increasing the outflow of a wide range of chemotherapeutic agents from human cancer cells, such as esophageal squamous cell carcinoma [152], osteosarcoma [153], and hepatocellular carcinoma [154]. A similar function of lncRNAs has also been explored in BC (Table 2). For instance, Chen et al. found that GAS5 was downregulated in adriamycin-resistant BC cells, while the mRNA ABCB1 was upregulated based on the RNA expression profiles. Further investigating the related mechanism in detail, GAS5 regulates its target Dickkopf 2 (DKK2) by working as a molecular sponge of miR-221-3p and inhibiting activation of the Wnt/β-catenin pathway [119]. The promoter of the ABCB1 gene contains TCF4/LEF binding motifs, which are targets of β-catenin/TCF4 transcriptional regulators [155]. Therefore, the downregulation of GAS5 will disinhibit the Wnt/β-catenin pathway, increase the expression of ABCB1, and promote the exit of adriamycin from intracellular sources. With the function of regulating drug efflux metabolism, targeting lncRNAs may become a promising approach to eliminate or suppress MDR by reducing drug efflux from tumor cells. Ideally, the combination of chemotherapeutic drugs and lncRNA target drugs can reduce the dose and side effects for BC patients.

5.5. Epigenetic Modification

Epigenetic factors, such as chromatin remodeling and DNA methylation, are related to the spatial and temporal regulation of gene expression [174,175]. Therefore, a malignant phenotype may be induced by aberrant expression patterns or genomic alterations in chromatin remodelers. Although it has been reported that epigenetic factors contribute greatly to drug tolerance [176–178], most of the exact mechanisms behind these associations remain elusive. In this section, we summarized that lncRNAs regulate gene expression via epigenetic modification in chemoresistant BC cells (Table 2). As shown in Figure 7, the expression of Linc00969 was upregulated in trastuzumab-resistant cells [137]. Then, Linc00969 could increase the translation of ERBB2 mRNA by binding to the Hu antigen R (HUR) protein. Therefore, the protein level of HER-2 was upregulated and, subsequently, induced trastuzumab resistance in HER-2+ BC cells. As one of the most common epigenetic modifications, histone acetylation can neutralize lysine’s positive charge to relax the chromatin structure and enhance transcriptional activity [179]. It has been reported that ZNF649-AS1, upregulated by H3K27ac modification, confers trastuzumab resistance by binding PTBP1 and upregulating ATG5 transcription [61]. Similarly, Dong et al. used chromatin immunoprecipitation (ChIP) assays and found that lncRNA SNHG14 can modulate H3K27 acetylation at the promoter region of the PABPC1 gene and can increase the transcription of PABPC1 [142]. Increasing the expression of PABPC1 activates the Nrf2 pathway and, then, promotes tumorigenesis and trastuzumab resistance in BC cells. Consequently, even in the same cell line exposed to the same treatment, different lncRNAs may have similar functions (e.g., guides) via different pathways. In brief, lncRNAs could play a critical biological function in regulating the expression of genes. Further research is needed to explore the deeper underlying mechanism of epigenetic modification-related lncRNAs in MDR.

5.6. Modifying the TME via Exosomal lncRNAs

The TME is a complex system comprising tumor cells, stromal cells (cancer-associated fibroblasts, endothelial cells, and macrophages), extracellular matrix, and soluble factors (hormones, cytokines, and enzymes) [180]. The TME not only plays an important role in the process of tumorigenesis, proliferation, and metastasis but also has a profound impact on chemotherapeutic efficacy. Exosomes, ranging in size from 20 to 150 nm, are membrane-derived vesicles originating from endosomal multivesicular bodies (MVBs) and play an essential role in TME. They can transfer useful information from host cells to recipient cells, such as lipids, proteins, microRNAs (miRNAs), messenger RNAs (mRNAs), and lncRNAs [181–183]. Thus, exosomal lncRNAs have been investigated to explore the mechanisms of MDR in different types of tumors, such as renal cancer [184], lung cancer [185], esophageal squamous cell carcinoma [186], BC (Table 3), gastric cancer [187], ovarian cancer [188], and cervical cancer [189].

Until now, few studies have addressed the link between exosomal lncRNAs and chemoresistance in BC (Table 3). As shown in Figure 7, Liu et al. reported that exosomes from trastuzumab-resistant cells packaged extracellular Linc00969 and transferred it to trastuzumab-sensitive cells, which also resulted in upregulation of the HER-2 protein and induced resistance of recipient cells [137]. It has been reported that exosomes produced by tamoxifen-resistant LCC2 cells containing more UCA1 are incorporated into MCF-7 cells and then significantly increase tamoxifen resistance in ERα-positive BC cells [190]. Notably, lncRNAs in exosomes derived from chemoresistant BC cells could confer resistance to sensitive cells, even in different cell lines. Additionally, the infiltration of immune cells into TME plays an indispensable role in the anti-tumor process. Ni et al. reported that the expression of CD73 on γδT cells (a predominant type of regulatory T cells) could be upregulated by lncRNA SNHG16, which is transmitted via BC-derived exosomes [191]. This is closely related to unfavorable pathological characteristics and a poor prognosis of BC. Based on these reports, transmission of exosomes might provide a new idea for drug therapy, which could change the susceptibility of cells to chemotherapeutic drugs or reverse the immunosuppressive microenvironment for more effective immunotherapy.

7.1. Association of lncRNAs and Patients with BC

Indeed, existing studies are not limited to in vitro cellular and animal experiments. Many studies have also explored the relationship between lncRNAs and patients [119,137,192]. The following two situations are common: In the first case, significant differences were found in BC tissues from patients, and further experimental verification was carried out. For instance, Chen et al. collected 26 BC tissue samples from patients and compared the expression of GAS5 and ABCB1 between tissues from responders and nonresponders [119]. Then, they verified that GAS5 and ABCB1 expression was downregulated in chemoresistant patients and cell lines, indicating a positive correlation. In the second case, significant differences were first found by in vitro cellular and animal experiments and then further validated in BC patients. For instance, lncRNA H19 was upregulated in doxorubicin-resistant cells, as reported by Wang et al. [192]. Then, they verified this result in BC patients by statistical analysis and reported that the exosomal lncRNA H19 may be a noninvasive biomarker for doxorubicin-resistant BC patients. Briefly, some lncRNAs that are differentially expressed in cell lines are also consistent in the BC tissues of patients who received chemotherapy. The limitations of these studies are related to the small samples of patients and the lack of statistical analysis of sensitivity and specificity for lncRNAs serving as biomarkers. To achieve clinical application, further experiments and larger-scale clinical trials are needed.

The authors state that the scientific conclusions are unaffected. The correction was approved by the Academic Editor. The original publication has also been updated.