Next Article in Journal
mTOR Regulation of N-Myc Downstream Regulated 1 (NDRG1) Phosphorylation in Clear Cell Renal Cell Carcinoma
Next Article in Special Issue
Does Diffusely Infiltrating Lobular Carcinoma of the Breast Arise from Epithelial–Mesenchymal Hybrid Cells?
Previous Article in Journal
A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 11
10.3390/ijms24119360
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Mechanism of DNA Methylation and miRNA in Breast Cancer

by
Lingyuan Ma
1,2,†,
Chenyu Li
1,2,†,
Hanlin Yin
1,2,
Jiashu Huang
1,2,
Shenghao Yu
1,2,
Jin Zhao
1,2,
Yongxu Tang
1,2,
Min Yu
1,2,
Jie Lin
1,2,
Lei Ding
1,2,* and
Qinghua Cui
1,2,*
1
Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China
2
Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(11), 9360; https://doi.org/10.3390/ijms24119360
Submission received: 7 April 2023 / Revised: 17 May 2023 / Accepted: 25 May 2023 / Published: 27 May 2023
(This article belongs to the Special Issue Molecular Mechanism of Cancer Research and Therapies)
Browse Figure
Review Reports Versions Notes

Abstract

:
Breast cancer is the most prevalent cancer in the world. Currently, the main treatments for breast cancer are radiotherapy, chemotherapy, targeted therapy and surgery. The treatment measures for breast cancer depend on the molecular subtype. Thus, the exploration of the underlying molecular mechanisms and therapeutic targets for breast cancer remains a hotspot in research. In breast cancer, a high level of expression of DNMTs is highly correlated with poor prognosis, that is, the abnormal methylation of tumor suppressor genes usually promotes tumorigenesis and progression. MiRNAs, as non-coding RNAs, have been identified to play key roles in breast cancer. The aberrant methylation of miRNAs could lead to drug resistance during the aforementioned treatment. Therefore, the regulation of miRNA methylation might serve as a therapeutic target in breast cancer. In this paper, we reviewed studies on the regulatory mechanisms of miRNA and DNA methylation in breast cancer from the last decade, focusing on the promoter region of tumor suppressor miRNAs methylated by DNMTs and the highly expressed oncogenic miRNAs inhibited by DNMTs or activating TETs.

1. Introduction

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide [1]. BC can be divided into five subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2) and other biomarkers—Luminal A, Luminal B, HER2-enriched, basal-like and a Normal Breast-like Group [2,3]. Hormonal therapy is commonly used for ER-positive breast cancer patients, but it usually causes the development of drug resistance [4], and the newly adjuvant chemotherapy can reduce mortality in breast cancer patients [5]. Targeted therapy is the most effective regimen recognized for the treatment of HER2+ breast cancer [6]. Case in point, trastuzumab, the first FDA-approved recombinant antibody, is used extensively to target HER2-positive breast cancer [7]. Immunotherapy has been proven to ameliorate patient prognosis and survival as well [8]. Nevertheless, the combination of chemotherapy and radiotherapy is the most important treatment for triple negative breast cancer (TNBC) defined as ER-, PR- and HER2-negative [8,9]. The therapy combination faces challenges due to the high heterogeneity, high rates of metastasis, poor prognosis and lack of therapeutic targets for TNBC [10]. Therefore, the pathogenesis of BC needs more exploration. Currently, the role of epigenetic alterations, such as DNA methylation and microRNA (miRNA), has become a fascinating area in relation to regulating gene expression at the pre- or post-transcriptional levels, which might offer a new opportunity for cancer clinical management in BC. In this review, we aim to summarize the roles of DNA methylation and miRNA in BC initiation, development and clinical therapeutics, and to review the relationship between miRNA and DNA methylation to identify potential therapeutic targets for breast cancer.

2. The Dysregulation of DNA Methylation in Breast Cancer

Epigenetics is a heritable molecular mechanism that regulates gene expression without altering the actual sequence of DNA, and it includes epigenetic regulations caused by DNA methylation, histone modification, chromatin remodeling and RNA-mediated gene targeting [11]. The alterations of epigenetics can regulate a number of molecular, cellular and biological pathways associated with breast carcinogenesis [12]. Studies have shown that the causes of thyroid cancer [13], lung cancer [14], liver cancer [15], gastric cancer [16], prostate cancer [17], bladder cancer [18], ovarian cancer [19], colorectal cancers [20] and breast cancer [21] are associated with abnormal methylation, and it can be said that almost all cancers are associated with abnormal DNA methylation. In this article, we focus on the abnormal regulation of DNA methylation in BC. DNA methylation involves adding methyl groups to cytosine via three DNA methyltransferases (DNMTs)—DNMT1, DNMT3A and DNMT3B—without changing the DNA sequence [22,23]. Abnormal methylation includes local hypermethylation of the promoter region in the CpG island of a specific gene and whole-genome hypomethylation in the genomic repeat regions [24] associated with malignant tumors [25,26], or the specific hypomethylation of some genes [24], such as signal-induced proliferation-associated protein 1 (SIPA1) [27].

2.1. DNA Hypermethylation in Breast Cancer

In mammals, methylation sites are primarily located on the CpG island in the promoter regions of genes [28]. When methylation occurs in the promoter region of a gene, transcription is inhibited directly by blocking the binding sites for the transcription factor or by recruiting methyl–CpG binding proteins [29]. Large amounts of evidence have shown that the DNA methylation level in BC cells is dramatically increased compared to that in normal cells. The hypermethylation of tumor suppressor genes (TSGs) promotes uncontrolled cell proliferation, resulting in metastasis, which can be used as a biomarker for breast cancer diagnosis and treatment [30,31,32]. Glutathione S-transferase Mu 2 (GSTM2) has been identified in aggressive, high-grade breast tumors where promoter hypermethylation is associated with ER/PR-negative status among ductal carcinoma in situ (DCIS) and invasive tissue components [33]. The expression of the tumor suppressor gene superoxide dismutase3 (SOD3) is downregulated in breast cancer; therefore, SOD3 expression levels are inversely correlated to its promoter CpG methylation, which is significantly associated with poor outcome patients [34].

2.2. DNA Hypomethylation in Breast Cancer

Regional DNA hypomethylation also occurs in cancer, and the frequency of this is lower than that of regional DNA hypermethylation [35]. A reduced probability of cytosine being methylated during the global DNA hypomethylation of tumor genomes corresponds to an average loss of about 5% to 20% of 5mC bases [36]. In the early stages of cancer, the DNA hypomethylation of non-coding repetitive elements is a shared trait of tumor cells [37]. DNA hypomethylation occurs in about 50% of breast cancers [38,39], and correlates to histologic grade stage and malignancy [40]. DNA methylation is regulated by the balance of DNMTs and DNA demethylases (TETs). Two patterns of hypomethylation occur in BC—one resulting in the hypomethylation of aberrant oncogenes by demethylases, and the other resulting in reduced levels of oncogene methylation due to the absence of DNA methylation. The TETs (TET1, TET2 and TET3) are DNA demethylation enzymes that convert 5 methyl-cytosine (5mC) into 5 hydroxymethylcytosine (5hmC) [41].
In TNBCs, TET1 causes DNA hypomethylation and the activation of oncogenic signaling pathways [42]. Estrogen (17β estradiol; E2) induces DNMT3B-mediated hypomethylation in the promoter of the Yes-associated protein-1 (YAP1) and augments proliferation [43]. The overexpression of the potassium two pore domain channel subfamily K member 9 (KCNK9/TASK3) protein by the hypomethylation of KCNK9 differential methylation region (DMR) elevates mitochondrial membrane potential and inhibits apoptosis [44]. The increased expression of signal-induced proliferation-associated protein 1 (SIPA1) caused by the hypomethylation of the CpG island in the promoter-proximal element ultimately promotes epithelial–mesenchymal transformation (EMT) [27]. The methylation of the ADAM metallopeptidase domain 12 (ADAM12) in TNBC is lower than that in Non-Neoplastic Breast Tissues. Hypomethylation could be a poor outcome biomarker and a potential therapeutic target [45]. Long-disseminated non-coding element 1 (LINE-1) hypomethylation is reported as a biomarker for patients with low-grade BC [46].

3. Aberrant Methylation Associated with Drug Resistance in Breast Cancer

Chemotherapy, surgery and radiation therapy are currently the main pillars of cancer treatment [47]. However, drug resistance due to abnormal methylation limits the efficacy of these therapies [48].

3.1. Hypermethylation of Genes Associated with Drug Resistance in Breast Cancer

The changes in the DNA methylation status of the promoters of certain genes correlate with drug resistance in breast cancer (as shown in Table 1). The hypermethylation of glucosylceramide synthase (GCS) enhances drug resistance [49]. In patients with ER-positive breast cancer, endocrine therapy works by blocking the attachment of estrogen to ER. Endocrine resistance is related to the methylation of estrogen receptor 1 (ESR1) in cell-free DNA (cfDNA) [50]. The hypermethylation of the spalt-like transcription factor 2 (SALL2) promoter results in tamoxifen resistance [51]. The abnormal DNA methylation of bone morphogenetic protein 6 (BMP6), crucial to the EMT phenotype, contributes to doxorubicin resistance [52]. In HER2-positive breast cancer patients, the first targeted drug to be approved is trastuzumab [53]; however, a large number of patients have shown primary or acquired resistance, which is significantly related to the hypermethylation of the tumor suppressor gene transforming growth factor beta induced (GFBI) promoter [54]. Oftamoxifen resistance is associated with the methylation aberration of the paired box 2 (PAX2) promoter [55]. ERα methylation develops cisplatin resistance [56], while docetaxel resistance is caused by the methylation of the Ras association domain family member 10 (RASSF10) [57].

3.2. Hypomethylation of Genes Associated with Drug Resistance in Breast Cancer

Epigenetic changes in breast cancer, including altered levels of methylation at the CpG site, are normally located on the promoter of the genes, and have been linked with resistance to some chemotherapeutic agents (as shown in Table 2). In the MCF-7 cell line, tamoxifen resistance is caused by the hypomethylation of CpG islands of the lactate dehydrogenase B (LDHB) promoter [58]. In the tumor and serum of patients with invasive ductal breast cancer, increases in tumor size and advanced tumor stage were significantly correlated with the hypomethylation of Multi-Drug Resistance Gene-1 (MDR1) [59]. The hypomethylation of matrix metallopeptidase 1 (MMP1) may be the cause of tamoxifen resistance in breast cancer. In tamoxifen-resistant MCF-7 cells, it was found that MMP1 was hypomethylated and over-expressed. The downregulation of MMP1 enhances sensitivity to tamoxifen and increases cell apoptosis [60]. Studies have shown that, compared with the TNBC samples before treatment, the hypomethylation of the SH3 domain containing GRB2-like 2 (SH3GL2) promoter in neoadjuvant chemotherapy-treated (NACT) samples leads to the downregulation of epidermal growth factor receptor (EGFR) protein, and finally, the nuclear expression of Y654-p-β-catenin in NACT samples decreases, resulting in a low proliferation index/CD44 prevalence rate. Therefore, the hypomethylation of the SH3GL2 promoter plays an important role in the chemical tolerance of TNBC [61].

4. MiRNA and DNA Methylation

MiRNAs are small non-coding RNA with a length of 18 to 25 nucleotides [62]. MiRNA biogenesis involves three main steps: firstly, the fragment located in an intragenic region or gene desert is transcribed by RNA polymerase II (pol II), which produces an mRNA with a length of about 3000 to 5000 bases, called primary miRNA (pri-miRNA). In the second step, pri-miRNA is shortened to produce a 70-base precursor miRNA (pre-miRNA), which is shortened by DROSHA and DGCR8. Finally, the export receptor export 5 (Exp5) directly interacts with the pre-miRNA to transport it into the cytoplasm, and then the Dicer cleaves the pre-miRNA into short fragments with a length of 22 bases. Then, its double strand is dissociated into a single strand. AGO-2 is connected with one of the mature strands to form an RNA-induced silencing complex (RISC) [62,63,64,65]. The process is as shown in Figure 1. According to the miRNAs’ progression- or suppression-promoting function, they can be used as oncogenes or as tumor suppressors, respectively [66]. One example is miR-125b, which is downregulated in breast-cancer-promoting cell proliferation and cell-cycle progression [67].
Under the action of pol II, the DNMTs gene undergoes intron shearing, exon splicing and a series of complex processes, before finally becoming mature messenger RNA (mRNA) [65], as shown in Figure 1. Studies have shown that DNMT1, DNMT3A and DNMT3B are usually highly expressed in patients with advanced breast cancer [63]. The hypermethylation of the CpG-rich promoter regions of tumor suppressor miRNAs usually leads to their silencing [68] through DNMTs. The hypomethylation of oncogenic miRNAs was downregulated in breast cancer. The abnormal DNA methylation of miRNA usually leads to the downregulation of miRNA, which is significantly related to the malignant phenotype of breast cancer cells [69]. In turn, miRNA could regulate the expression level of the target gene after transcription, which affects DNA methylation in breast cancer cells through the 3′ untranslated region (3′-UTR) of the RISC-targeted DNMTs’ mRNA [70]. In conclusion, this demonstrates the existence of a regulatory loop between miRNA expression and epigenetic modifications [71].

5. The Relationship between miRNA and DNA Methylation

In breast cancer, there are three patterns of miRNA and DNA methylation. The first is the epigenetic silencing of miRNAs to inhibit the transcription of miRNAs, by which DNMTs downregulate the expression of miRNAs through methylation in the promoter region of miRNAs, which are usually suppressor miRNAs. The second is that miRNAs inhibit the expression of DNMTs, where miRNAs (generally suppressor miRNAs) target the 3′-UTR region of DNMTs through RISC to inhibit the expression of DNMTs. The third type is the abnormal hypomethylation of oncogenic miRNAs that are highly expressed in breast cancer and thus promote its development.

5.1. Aberrant Methylation of Tumor Suppressor miRNA Promoter in Breast Cancer

In breast cancer, tumor suppressor miRNAs epigenetically silenced by DNMTs are usually involved in cell proliferation, migration, invasion and stemness, as well as cell apoptosis, and can be used as clinical markers (as shown in Table 3). MiR-29c inhibits tumor growth by regulating TGFB-induced factor homeobox 2 (TGIF2), CAMP-responsive element binding protein 5 (CREB5), and V-Akt murine thymoma viral oncogene homolog 3 (AKT3). The miR-29c is gradually downregulated via DNA methylation in the promoter region involved in the occurrence and development of tumors [72]. Flap structure-specific endonuclease 1 (FEN1) promotes miR-200a methylation by forming an FENl/PCNA/DNMT3A complex that inhibits the signal transduction of MET proto-oncogene, receptor tyrosine kinase (MET) and epidermal growth factor receptor (EGFR), thus repressing cell proliferation [73]. In aggressive breast cancer cell lines as well as untransformed mammary epithelial cells, the expression of the miR-200c/141 cluster is regulated by DNA methylation, and the epigenetic silencing of the miR-200c/141 cluster induces EMT [74]. The hypermethylation of the miR-203 promoter downregulates its expression in highly aggressive breast cancer cells. The overexpression of miR-203 inhibits tumor cell invasion by preventing the mesenchymal marker snail family transcriptional repressor 2 (Snail2) [75].
However, some other oncogenic miRNAs have multiple functions in breast cancer development. In a previous study, miR-195/497 was proven to have an inhibitory effect on breast cancer malignancies [76]. MiR-195/497 targets mucin1 (MUC1) and promotes the apoptosis of breast cancer cells by downregulating MUC1. In breast cancer tissues and cells, the methylation of CpG islands of the miR-195/497 promoter reduces the expression of miR-195/497 and promotes proliferation and invasion [77]. In TNBC, methylation on the CpG island of miR-296-5p and miR-512-5p improves the expression level of downstream target gene telomerase reverse transcriptase (hTERT), which is involved in inhibiting cell apoptosis and improving invasiveness [78]. MiR-31 inhibits metastasis and is highly expressed in early BC; as the tumor progresses to a more aggressive stage, the expression level of miR-31 is reduced and becomes undetectable in metastatic BC [79]. The loss of miR-31 expression in TNBC cell lines is attributed to promoter hypermethylation [80]. In breast cancer clinical samples and cell lines, promoter hypermethylation of miR-145 and direct targeting of the angiopoietin 2 (AngpT2) gene have been found. AngpT2 is a member of the angiopoietin family that promotes tumor development and progression by linking metastatic inflammasomes to angiogenic processes. The methylation of miR-145 silences its expression and leads to the upregulation of AngpT2, promoting migration and invasion [81]. MiR-133a-3p is epigenetically suppressed and silenced by promoter methylation, which leads to a significant increase in the proliferation, migration, invasion and stemness of breast cancer cells in vitro, mainly through the miR-133a-3p/MAML1/DNMT3A positive feedback loop [82]. In the nucleus of the breast cancer cell, Kindlin 2 forms a complex with DNMT3A, which occupies the promoter of miR-200b to promote cell invasion migration and stemness [83]. The above-mentioned oncogenic miRNAs in breast cancer are usually down-regulated through epigenetic silencing, and have only oncogenic function according to the literature.
Epigenetically silenced miRNAs can not only affect the development of breast cancer, but also serve as clinical markers of breast cancer. The studies show that the high methylation of miR-124a-1/2/3 plays an important role in tumor growth and invasion [84]. MiR-132, miR-137 and miR-1258, with hypermethylation frequencies of 41%, 37% and 34%, respectively, were found to be associated with clinical features in a representative sample of 41 breast cancers [85]. Others have analyzed 91 representative samples of breast cancer and histologically normal tissues, showing that the hypermethylation of miR-9-3 and miR-339 is related to tumor size, and the hypermethylation of six miRNA genes (miR-124-1, miR-127, miR-34B/C, miR-9-3, miR-1258 and miR-339) was found to be significantly related to the late (III–IV) clinical stage [86].
There are also some epigenetically silenced miRNAs with unknown functions in breast cancer. The erb-b2 receptor tyrosine kinase 2 (ErbB2) signal induces the DNMTs family through the Ras/Raf/MEK/ERK pathway, leading to the hypermethylation of the CpG-rich region of the miR-205 promoter, which in turn inhibits the transcription of miR-205 [87]. In cervical cancer, miR-152 acts as an oncogene to promote the growth, survival, migration and aggressiveness of cancer cells [88]. In 71 primary human breast cancer specimens, the effect of demethylation on miRNA gene expression was that 34–86% of cases showed abnormal hypermethylation of miR-9-1, miR-124a3, miR-148, miR-152 and miR-663 [89]. MiR-9-1, miR-148, miR-152 and miR-663 can act as tumor suppressors in many cancers; miR-9-1 inhibits nasopharyngeal carcinoma growth and glucose metabolism [90]; miR-148 and miR-152 can inhibit the proliferation of prostate cancer cells [91]; and miR-663 suppresses the proliferation and invasion of colorectal cancer cells by directly targeting FSCN1 [92].

5.2. The DNMTs Targeted by Tumor Suppressor miRNA to Deregulate DNA Methylation

In breast cancer, a high expression of DNMTs relates to the occurrence and development of breast cancer. Partially overexpressed tumor suppressor miRNAs could directly target and inhibit the expression of DNMTs, decreasing cell proliferation, migration, invasion and EMT (as shown in Table 4) and ultimately slowing down the development of breast cancer. MiR-152 targets DNMT1 and downregulates the expression of DNMT1, which helps restore cadherin 1 (CDH1) gene expression and obstructs the migration of breast cancer cells [93]. MiR-148a regulates the DNA methylation of ER-α by targeting DNMT1 [94]. Phosphatase and tensin homolog (PTEN), a tumor suppressor also methylated by DNMT3A, is a direct target of miR-143 [95]. In breast cancer tissues and breast cancer cell lines, the expression of miR-101 is downregulated and the expression of DNMT3A is upregulated. It has been found that miR-101 inhibits cell proliferation and migration by inhibiting DNMT3A, thus restoring the expression of E-cadherin [96]. MiR-194 targeted DNMT3A in BC, and the increased expression of miR-194 stimulated tumor suppressor cyclin G2, p27Kip1 and ADAM metalpeptidase domain 23 (ADAM23), leading to inhibited cell motility [97]. In TNBC, E-cadherin protein, encoded by CDH1, mediates intercellular adhesion. MiR-770-5p has been found to target and block the activity of DNMT3A, which is responsible for the hypermethylation of the CDH1 promoter. The re-expression of miR-770-5p restores E-cadherin expression by targeting DNMT3A, thus reversing EMT to mesenchymal–epithelial transition (MET) [98]. In ER-positive breast cancer cells, miR-29c-5p downregulates DNMT3A, resulting in the hypomethylation of CpG in ER-related transcription factor binding site (TFBS). The CpG sites are located in TFBS enhancer regions of ER-α, forkhead box A1 (FOXA1) and GATA binding protein 3 (GATA3). All of these genes are key factors determining the phenotypes of luminal breast cancer [99]. In breast cancer cells, miR-29c targets and downregulates DNMT3B and reduces the DNA methylation level of TIMP metallopeptidase inhibitor 3 (TIMP3). Finally, the proliferation, migration, invasion, colony formation and growth of breast cancer are mediated by TIMP3/STAT1/FOXO1 [100]. MiR-148b, miR-29c and miR-26b target DNMT3B and prevent the expression of DNMT3B [101]. In human breast cancer stem cells (BCSC), miR-221 downregulates the expression of DNMT3B and changes the phenotype. DNMT3B inhibits the expression of Nanog and Oct 3/4 and increases the cell numbers. Therefore, the downregulation of DNMT3B may represent an advantage for cancer development and promote the expansion of stem cell compartment [102]. In non-invasive epithelial breast cancer cells, the low expression of miRNA-29b inhibits cell proliferation and decreases DNMT3A and DNMT3B mRNA, following reductions in the promoter methylation of ADAM metallopeptidase domain 23 (ADAM23) [103], cyclin A1 (CCNA1) [104], cyclin D2 (CCND2) [105], CDH1 [106], cyclin-dependent kinase inhibitor 1C (CDKN1C) [107], cyclin-dependent kinase inhibitor 2A (CDKN2A) [108], HIC ZBTB transcriptional repressor 1 (HIC1) [109], Ras association domain family member 1 (RASSF1) [110], slit guidance ligand 2 (SLIT2) [111], TNF receptor superfamily member 10d (TNFRSF10D) [112], and tumor protein p73 (TP73) [113] tumor-suppressor genes, which improves breast cancer therapy [70]. In TNBC, the overexpression of miR-29B-1-5p inhibits the expression of DNMTs, followed by inhibiting the promoter methylation modification of tumor suppressor genes (TSG) secretoglobin family 3A member 1 (SCGB3A1/HIN1), Ras association domain family member 1 (RASSF1A) and CCND2, and inhibiting cell growth [114].

5.3. Hypomethylation of miRNA in Breast Cancer

The hypomethylation of aberrant miRNAs is uncommon in breast cancer, but it still affects cancer development. Aberrant oncogenic miRNAs may activate the oncogenic pathways by inducing demethylases (TETs) or inhibiting the expression of methylation transferases DNMTs, ultimately leading to the upregulation of oncogenic miRNAs and promoting cancer development. In an ERα-positive breast cell line, miR-375 is highly expressed and hypomethylated. It targets Ras-related dexamethasone-induced 1 (RASD1), inhibits ERα activation and induces cell proliferation [115]. The overexpression of the methyl-CpG-binding domain protein 2 (MBD2) in MCF-10A leads to the demethylation of miR-496, while the depletion of MBD2 in MCF-7 and MDA-MB-231 inhibits the expression of miR-496 [116]. MiR-21 is an oncogenic miRNA that is upregulated in breast cancer. DNA methylation regulates the expression of miR-21 by knocking out the DNA demethylases TET3, and thymine DNA glycosylase (TDG) reduces the expression of miR-21 [117]. In young women with breast cancer, the promoter of miR-124-2 is usually demethylated, and therefore miR-124-2 is identified as a survival biomarker of breast cancer [118].

6. Aberrant Methylation of miRNAs Leads to Drug Resistance in Breast Cancer

The aberrant methylation of miRNAs is closely related to chemotherapy resistance, affecting cell cycle, DNA damage repair, apoptosis, stem cell transformation and mesenchymal transformation [119]. In drug-resistant breast cancer, aberrant tumor suppressor promoter hypermethylation and oncogenic miRNA hypomethylation leads to the dysregulation of oncogenic miRNA, ultimately leading to drug resistance.

6.1. Hypermethylation of miRNAs Leads to Drug Resistance in Breast Cancer

In breast cancer, the abnormal methylation of miRNA is one of the reasons for drug resistance, whereby the sensitivity of cells to drugs decreases, and this is mainly manifested as breast cancer proliferation, migration, invasion and colony formation, as shown in Table 5. In tamoxifen-resistant (TamR) MCF-7 cells, the methylation level of the miR-27b promoter region is significantly higher than that of tamoxifen-sensitive (TamS) MCF-7 cells. The re-expression of miR-27b restores drug sensitivity, inhibits invasion and reverses the EMT-like trait [120]. In addition, miR-29s, miR-132 and platinum-based chemotherapy affect DNA methylation [121]. Furthermore, endocrine resistance can be produced by the expression of miR-200b and miR-200c, while the anti-methylation drug 5-aza-dC+TSA can reduce the expression of miR-200 family members, thereby restoring the sensitivity of cancer cells to endocrine therapy [122]. MiR-320, as a mediator of chemoresistance, directly targets transient receptor potential cation channel subfamily C member 5 (TRPC5) and nuclear factor of activated T cells 3 (NFATC3), and the expression of miR-320a is regulated by the methylation of the promoter and ETS proto-oncogene 1 transcription factor (ETS-1) [123].

6.2. Hypomethylation of miRNAs Leads to Drug Resistance in Breast Cancer

In drug-resistant breast cancer, the aberrant hypomethylation of oncogenic miRNAs and the higher expression of miRNAs trigger oncogenic pathways, leading to the loss of breast cancer sensitivity to chemotherapeutic agents and promoting tumorigenesis and progression, as shown in Table 6. For example, tamoxifen reverses the EMT in TNBC cells via miR-200c demethylation [124]. It has been reported that the demethylation of miR-663 is related to the chemical resistance of breast cancer, including chemotherapy with doxorubicin, docetaxel and cyclophosphamide, and demethylation of the miR-663 promoter region upregulates the miR-663 expression level in breast cancer cells [125]. In addition, studies have found that downregulating miR-93 increases apoptosis in BC cells. A higher proliferation rate and lower apoptosis rate are observed in drug-sensitive cells with miR-93 overexpression. The methylation level of miR-93 is significantly low in drug-resistant cells with seven specific CpG sites of methylation [126].

7. Conclusions and Perspective

In this review, we highlight the oncogenic mechanisms of miRNA and DNA methylation in breast cancer. Oncogenic miRNA is highly expressed by inhibiting DNMTs or activating TETs, while suppressor miRNAs target DNMTs in breast cancer. Both the methylation of the miRNA promoter region and miRNAs’ regulating effects on DNMTs play important roles in breast cancer development and drug resistance, which may provide new therapeutic targets for drug resistance in breast cancer.
The two oncogenic mechanisms of miRNA and DNA methylation provide new strategies for breast cancer treatment. From February 2016 to April 2019, the General Surgery Department completed a clinical study with 20 unifocal and 20 multifocal breast cancer patients’ tissue samples, which were selected to analyze the expression of 84 microRNAs (Clinical Trials: NCT04516330). In December 2021, the Irish Cancer Trials completed a clinical trial to identify miRNA biomarkers that could be used to monitor patient response to chemotherapy and hormone therapy (Clinical Trials: NCT01612871). These clinical studies all suggest that specific miRNAs may be present in breast cancer patients with different types, stages and treatment cycles, and they may serve as biomarkers for individualized treatment. Aberrant miRNAs in breast cancer, including those caused by methylation, also appear to serve as biomarkers for breast cancer, offering possibilities for individualized breast cancer treatment.
With more understanding of the mechanisms of aberrant DNA hypermethylation in breast cancer, new therapeutic targets and new epigenetic treatment strategies will emerge. These targets for treatment may include DNMTs or other components of the DNA methylation machinery. Currently, there are two DNA Methyltransferase Inhibitors (DNMTis)—azacytidine and decitabine—approved for treating patients affected by myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML), while others are being trialed in multiple forms. Much effort is being made to improve efficacy through combining DNMTs with other therapies. Recent studies combining DNMTi with radiotherapy may provide a new treatment pathway for patients, especially for those who cannot tolerate platinum-based chemoradiotherapy [127].
Currently, there are many RNAi drugs. However, research into using miRNA-mimicking drugs in breast cancer clinical therapy is rare. Needless to say, the discovery of the importance of miRNAs in gene regulation and their association with cancer and other diseases has made them important targets for drug development. However, for nucleotide-based drugs, the greatest barriers to their action in vivo are degradation by nucleases and the escape of drug molecules from endosomes during endocytosis. The potential immunostimulatory effects and the lack of target specificity to the lesion area also represent other significant challenges for drug delivery systems [128]. The development of miRNA-targeted DNMT-induced tumors can be achieved by promoting the expression of miRNAs, such as small-molecule drugs, which may lead to miRNA therapies. However, this may trigger a series of unknown and unpreventable consequences due to the multitude of miRNA downstream target genes.
There is a degree of circular regulation of the oncogenic mechanisms between miRNA and DNA methylation. The promoter region of miRNA is methylated by DNMTs, while miRNA also targets DNMTs to inhibit its expression, such as DNMT3B inducing miR-200b promoter methylation in TNBC. On the other hand, miR-200b would inhibit the expression of DNMT3B involved in breast cancer invasion, migration and mammosphere formation [129]. However, little has been reported so far, and this cyclic regulation mode raises a great challenge in the use of DNA methylation inhibitors or small-molecule drugs for miRNA BC clinic treatment.

Author Contributions

Conception and design—L.M., H.Y., C.L., L.D. and Q.C.; collection and/or assembly of data—L.M., H.Y., C.L., L.D. and Q.C.; manuscript writing—L.M., H.Y., C.L., L.D. and Q.C.; final approval of manuscript—all authors. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the National Natural Science Foundation of China (No. 32060161, U1902202, 3216050055), Yunnan Provincial Science and Technology Department grants (2019FA043), the Youth Project of Science and Technology Department of Yunnan Province (No. 202001BB050041), the Key Project of Science and Technology Department of Yunnan Province (No. 202001BB0500080), and the Project of Graduate Research Innovation of Yunnan University (No. 2021Y301, ZC-22223147).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Perou, C.M.; Sørlie, T.; Eisen, M.B.; van de Rijn, M.; Jeffrey, S.S.; Rees, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular Portraits of Human Breast Tumours. Nature 2000, 406, 747–752. [Google Scholar] [CrossRef] [PubMed]
  3. Harbeck, N.; Penault-Llorca, F.; Cortes, J.; Gnant, M.; Houssami, N.; Poortmans, P.; Ruddy, K.; Tsang, J.; Cardoso, F. Breast Cancer. Nat. Rev. Dis. Primer 2019, 5, 1–31. [Google Scholar] [CrossRef]
  4. Waks, A.G.; Winer, E.P. Breast Cancer Treatment: A Review. JAMA 2019, 321, 288–300. [Google Scholar] [CrossRef]
  5. Early Breast Cancer Trialists’ Collaborative Group. Effects of Chemotherapy and Hormonal Therapy for Early Breast Cancer on Recurrence and 15-Year Survival: An Overview of the Randomised Trials. Lancet 2005, 365, 1687–1717. [Google Scholar] [CrossRef]
  6. Masoud, V.; Pagès, G. Targeted Therapies in Breast Cancer: New Challenges to Fight against Resistance. World J. Clin. Oncol. 2017, 8, 120–134. [Google Scholar] [CrossRef] [PubMed]
  7. Barok, M.; Tanner, M.; Köninki, K.; Isola, J. Trastuzumab-DM1 Causes Tumour Growth Inhibition by Mitotic Catastrophe in Trastuzumab-Resistant Breast Cancer Cells in Vivo. Breast Cancer Res. BCR 2011, 13, R46. [Google Scholar] [CrossRef]
  8. Yang, R.; Li, Y.; Wang, H.; Qin, T.; Yin, X.; Ma, X. Therapeutic Progress and Challenges for Triple Negative Breast Cancer: Targeted Therapy and Immunotherapy. Mol. Biomed. 2022, 3, 8. [Google Scholar] [CrossRef]
  9. Kohler, B.A.; Sherman, R.L.; Howlader, N.; Jemal, A.; Ryerson, A.B.; Henry, K.A.; Boscoe, F.P.; Cronin, K.A.; Lake, A.; Noone, A.-M.; et al. Annual Report to the Nation on the Status of Cancer, 1975–2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State. Jnci-J. Natl. Cancer Inst. 2015, 107, Djv048. [Google Scholar] [CrossRef]
  10. Zhao, B.; Xu, Y.; Zhao, Y.; Shen, S.; Sun, Q. Identification of Potential Key Genes Associated with the Pathogenesis, Metastasis, and Prognosis of Triple-Negative Breast Cancer on the Basis of Integrated Bioinformatics Analysis. Front. Oncol. 2020, 10, 856. [Google Scholar] [CrossRef]
  11. Holliday, R. Epigenetics: An Overview. Dev. Genet. 1994, 15, 453–457. [Google Scholar] [CrossRef] [PubMed]
  12. Dawson, M.A.; Kouzarides, T. Cancer Epigenetics: From Mechanism to Therapy. Cell 2012, 150, 12–27. [Google Scholar] [CrossRef] [PubMed]
  13. Zafon, C.; Gil, J.; Perez-Gonzalez, B.; Jorda, M. DNA Methylation in Thyroid Cancer. Endocr. Relat. Cancer 2019, 26, R415–R439. [Google Scholar] [CrossRef] [PubMed]
  14. Hong, Y.; Kim, W.J. DNA Methylation Markers in Lung Cancer. Curr. Genom. 2021, 22, 79–87. [Google Scholar] [CrossRef]
  15. Bévant, K.; Desoteux, M.; Abdel Wahab, A.H.A.; Abdel Wahab, S.A.; Metwally, A.M.; Coulouarn, C. DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer. Cells 2021, 10, 2207. [Google Scholar] [CrossRef]
  16. Dai, J.; Nishi, A.; Li, Z.X.; Zhang, Y.; Zhou, T.; You, W.C.; Li, W.Q.; Pan, K.F. DNA Methylation Signatures Associated with Prognosis of Gastric Cancer. BMC Cancer 2021, 21, 610. [Google Scholar] [CrossRef]
  17. Zhao, S.G.; Chen, W.S.; Li, H.; Foye, A.; Zhang, M.; Sjostrom, M.; Aggarwal, R.; Playdle, D.; Liao, A.; Alumkal, J.J.; et al. The DNA Methylation Landscape of Advanced Prostate Cancer. Nat. Genet. 2020, 52, 778–789. [Google Scholar] [CrossRef]
  18. Nunes, S.P.; Henrique, R.; Jeronimo, C.; Paramio, J.M. DNA Methylation as a Therapeutic Target for Bladder Cancer. Cells 2020, 9, 1850. [Google Scholar] [CrossRef]
  19. Chiappinelli, K.B.; Baylin, S.B. Inhibiting DNA Methylation Improves Antitumor Immunity in Ovarian Cancer. J. Clin. Investig. 2022, 132, e160186. [Google Scholar] [CrossRef]
  20. Li, B.; Pan, R.; Zhou, C.; Dai, J.; Mao, Y.; Chen, M.; Huang, T.; Ying, X.; Hu, H.; Zhao, J.; et al. SMYD3 Promoter Hypomethylation Is Associated with the Risk of Colorectal Cancer. Future Oncol. 2018, 14, 1825–1834. [Google Scholar] [CrossRef]
  21. Prajzendanc, K.; Domagala, P.; Hybiak, J.; Rys, J.; Huzarski, T.; Szwiec, M.; Tomiczek-Szwiec, J.; Redelbach, W.; Sejda, A.; Gronwald, J.; et al. BRCA1 Promoter Methylation in Peripheral Blood Is Associated with the Risk of Triple-Negative Breast Cancer. Int. J. Cancer 2020, 146, 1293–1298. [Google Scholar] [CrossRef] [PubMed]
  22. Okano, M.; Bell, D.W.; Haber, D.A.; Li, E. DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development. Cell 1999, 99, 247–257. [Google Scholar] [CrossRef] [PubMed]
  23. Feng, L.; Lou, J. DNA Methylation Analysis. Methods Mol. Biol. 2019, 1894, 181–227. [Google Scholar]
  24. Kanwal, R.; Gupta, S. Epigenetic Modifications in Cancer. Clin. Genet. 2012, 81, 303–311. [Google Scholar] [CrossRef]
  25. Cao, W.; Lee, H.; Wu, W.; Zaman, A.; McCorkle, S.; Yan, M.; Chen, J.; Xing, Q.; Sinnott-Armstrong, N.; Xu, H.; et al. Multi-Faceted Epigenetic Dysregulation of Gene Expression Promotes Esophageal Squamous Cell Carcinoma. Nat. Commun. 2020, 11, 3675. [Google Scholar] [CrossRef]
  26. Tang, Q.; Cheng, J.; Cao, X.; Surowy, H.; Burwinkel, B. Blood-Based DNA Methylation as Biomarker for Breast Cancer: A Systematic Review. Clin. Epigenetics 2016, 8, 115. [Google Scholar] [CrossRef]
  27. Lu, A.; Wang, W.; Wang-Renault, S.-F.; Ring, B.Z.; Tanaka, Y.; Weng, J.; Su, L. 5-Aza-2′-Deoxycytidine Advances the Epithelial–Mesenchymal Transition of Breast Cancer Cells by Demethylating Sipa1 Promoter-Proximal Elements. J. Cell Sci. 2020, 133, jcs236125. [Google Scholar] [CrossRef]
  28. Deaton, A.M.; Bird, A. CpG Islands and the Regulation of Transcription. Genes Dev. 2011, 25, 1010–1022. [Google Scholar] [CrossRef]
  29. Bogdanovic, O.; Veenstra, G.J.C. DNA Methylation and Methyl-CpG Binding Proteins: Developmental Requirements and Function. Chromosoma 2009, 118, 549–565. [Google Scholar] [CrossRef]
  30. Hon, G.C.; Hawkins, R.D.; Caballero, O.L.; Lo, C.; Lister, R.; Pelizzola, M.; Valsesia, A.; Ye, Z.; Kuan, S.; Edsall, L.E.; et al. Global DNA Hypomethylation Coupled to Repressive Chromatin Domain Formation and Gene Silencing in Breast Cancer. Genome Res. 2012, 22, 246–258. [Google Scholar] [CrossRef]
  31. Esteve-Puig, R.; Bueno-Costa, A.; Esteller, M. Writers, Readers and Erasers of RNA Modifications in Cancer. Cancer Lett. 2020, 474, 127–137. [Google Scholar] [CrossRef] [PubMed]
  32. Baylin, S.B.; Jones, P.A. A Decade of Exploring the Cancer Epigenome—Biological and Translational Implications. Nat. Rev. Cancer 2011, 11, 726–734. [Google Scholar] [CrossRef] [PubMed]
  33. Kresovich, J.K.; Gann, P.H.; Erdal, S.; Chen, H.Y.; Argos, M.; Rauscher, G.H. Candidate Gene DNA Methylation Associations with Breast Cancer Characteristics and Tumor Progression. Epigenomics 2018, 10, 367–378. [Google Scholar] [CrossRef] [PubMed]
  34. Griess, B.; Klinkebiel, D.; Kueh, A.; Desler, M.; Cowan, K.; Fitzgerald, M.; Teoh-Fitzgerald, M. Association OfSOD3promoter DNA Methylation with Its Down-Regulation in Breast Carcinomas. Epigenetics 2020, 15, 1325–1335. [Google Scholar] [CrossRef] [PubMed]
  35. Veeck, J.; Esteller, M. Breast Cancer Epigenetics: From DNA Methylation to MicroRNAs. J. Mammary Gland Biol. Neoplasia 2010, 15, 5–17. [Google Scholar] [CrossRef]
  36. Pfeifer, G.P. Defining Driver DNA Methylation Changes in Human Cancer. Int. J. Mol. Sci. 2018, 19, 1166. [Google Scholar] [CrossRef]
  37. Switzer, C.H.; Cho, H.-J.; Eykyn, T.R.; Lavender, P.; Eaton, P. NOS2 and S-Nitrosothiol Signaling Induces DNA Hypomethylation and LINE-1 Retrotransposon Expression. Proc. Natl. Acad. Sci. USA 2022, 119, e2200022119. [Google Scholar] [CrossRef]
  38. Atalay, C. Epigenetics in Breast Cancer. Exp. Oncol. 2013, 35, 246–249. [Google Scholar]
  39. Ye, D.; Jiang, D.; Li, Y.; Jin, M.; Chen, K. The Role of LINE-1 Methylation in Predicting Survival among Colorectal Cancer Patients: A Meta-Analysis. Int. J. Clin. Oncol. 2017, 22, 749–757. [Google Scholar] [CrossRef]
  40. Szyf, M.; Pakneshan, P.; Rabbani, S.A. DNA Methylation and Breast Cancer. Biochem. Pharmacol. 2004, 68, 1187–1197. [Google Scholar] [CrossRef]
  41. Ito, S.; Shen, L.; Dai, Q.; Wu, S.C.; Collins, L.B.; Swenberg, J.A.; He, C.; Zhang, Y. Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine. Science 2011, 333, 1300–1303. [Google Scholar] [CrossRef] [PubMed]
  42. Good, C.R.; Panjarian, S.; Kelly, A.D.; Madzo, J.; Patel, B.; Jelinek, J.; Issa, J.-P.J. TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer. Cancer Res. 2018, 78, 4126–4137. [Google Scholar] [CrossRef] [PubMed]
  43. Muhammad, J.S.; Guimei, M.; Jayakumar, M.N.; Shafarin, J.; Janeeh, A.S.; AbuJabal, R.; Eladl, M.A.; Ranade, A.V.; Ali, A.; Hamad, M. Estrogen-Induced Hypomethylation and Overexpression of YAP1 Facilitate Breast Cancer Cell Growth and Survival. Neoplasia 2021, 23, 68–79. [Google Scholar] [CrossRef]
  44. Skaar, D.A.; Dietze, E.C.; Alva-Ornelas, J.A.; Ann, D.; Schones, D.E.; Hyslop, T.; Sistrunk, C.; Zalles, C.; Ambrose, A.; Kennedy, K.; et al. Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer. Cancers 2021, 13, 6031. [Google Scholar] [CrossRef] [PubMed]
  45. Mendaza, S.; Ulazia-Garmendia, A.; Monreal-Santesteban, I.; Cordoba, A.; Ruiz de Azua, Y.; Aguiar, B.; Beloqui, R.; Armendariz, P.; Arriola, M.; Martin-Sanchez, E.; et al. ADAM12 Is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2020, 21, 903. [Google Scholar] [CrossRef]
  46. Zeggar, H.R.; How-Kit, A.; Daunay, A.; Bettaieb, I.; Sahbatou, M.; Rahal, K.; Adouni, O.; Gammoudi, A.; Douik, H.; Deleuze, J.-F.; et al. Tumor DNA Hypomethylation of LINE-1 Is Associated with Low Tumor Grade of Breast Cancer in Tunisian Patients. Oncol. Lett. 2020, 20, 1999–2006. [Google Scholar] [CrossRef] [PubMed]
  47. Baskar, R.; Lee, K.A.; Yeo, R.; Yeoh, K.-W. Cancer and Radiation Therapy: Current Advances and Future Directions. Int. J. Med. Sci. 2012, 9, 193–199. [Google Scholar] [CrossRef]
  48. Tufail, M.; Cui, J.; Wu, C. Breast Cancer: Molecular Mechanisms of Underlying Resistance and Therapeutic Approaches. Am. J. Cancer Res. 2022, 12, 2920–2949. [Google Scholar]
  49. Liu, J.; Zhang, X.; Liu, A.; Zhang, D.; Su, Y.; Liu, Y.; You, D.; Yuan, L.; Kong, X.; Wang, X.; et al. Altered Methylation of Glucosylceramide Synthase Promoter Regulates Its Expression and Associates with Acquired Multidrug Resistance in Invasive Ductal Breast Cancer. Oncotarget 2016, 7, 36755–36766. [Google Scholar] [CrossRef]
  50. Bos, M.K.; Deger, T.; Sleijfer, S.; Martens, J.W.M.; Wilting, S.M. ESR1 Methylation Measured in Cell-Free DNA to Evaluate Endocrine Resistance in Metastatic Breast Cancer Patients. Int. J. Mol. Sci. 2022, 23, 5631. [Google Scholar] [CrossRef]
  51. Ye, L.; Lin, C.; Wang, X.; Li, Q.; Li, Y.; Wang, M.; Zhao, Z.; Wu, X.; Shi, D.; Xiao, Y.; et al. Epigenetic Silencing of SALL2 Confers Tamoxifen Resistance in Breast Cancer. EMBO Mol. Med. 2019, 11, e10638. [Google Scholar] [CrossRef] [PubMed]
  52. Liu, G.; Liu, Y.-J.; Lian, W.-J.; Zhao, Z.-W.; Yi, T.; Zhou, H.-Y. Reduced BMP6 Expression by DNA Methylation Contributes to EMT and Drug Resistance in Breast Cancer Cells. Oncol. Rep. 2014, 32, 581–588. [Google Scholar] [CrossRef] [PubMed]
  53. Carter, P.; Presta, L.; Gorman, C.; Ridgway, J.; Henner, D.; Wong, W.; Rowland, A.; Kotts, C.; Carver, M.; Shepard, H. Humanization of an Anti-P185her2 Antibody for Human Cancer-Therapy. Proc. Natl. Acad. Sci. USA 1992, 89, 4285–4289. [Google Scholar] [CrossRef] [PubMed]
  54. Palomeras, S.; Diaz-Lagares, A.; Vinas, G.; Setien, F.; Ferreira, H.J.; Oliveras, G.; Crujeiras, A.B.; Hernandez, A.; Lum, D.H.; Welm, A.L.; et al. Epigenetic Silencing of TGFBI Confers Resistance to Trastuzumab in Human Breast Cancer. Breast Cancer Res. 2019, 21, 79. [Google Scholar] [CrossRef]
  55. Jahangiri, R.; Mosaffa, F.; Emami Razavi, A.; Teimoori-Toolabi, L.; Jamialahmadi, K. PAX2 Promoter Methylation and AIB1 Overexpression Promote Tamoxifen Resistance in Breast Carcinoma Patients. J. Oncol. Pharm. Pract. 2022, 28, 310–325. [Google Scholar] [CrossRef] [PubMed]
  56. Xu, J.; Sun, T.; Guo, X.; Wang, Y.; Jing, M. Estrogen Receptor-α Promoter Methylation Is a Biomarker for Outcome Prediction of Cisplatin Resistance in Triple-Negative Breast Cancer. Oncol. Lett. 2018, 15, 2855–2862. [Google Scholar] [CrossRef]
  57. Dong, T.; Zhang, M.; Dong, Y.; Herman, J.G.; van Engeland, M.; Zhong, G.; Guo, M. Methylation of RASSF10 Promotes Cell Proliferation and Serves as a Docetaxel Resistant Marker in Human Breast Cancer. Discov. Med. 2015, 20, 261–271. [Google Scholar]
  58. Zhang, J.; Zhang, F.; Zhang, F.; Wu, H.; Zhang, B.; Wu, X. Correlation between Promoter Methylation of the LDH-C4 Gene and DNMT Expression in Breast Cancer and Their Prognostic Significance. Oncol. Lett. 2022, 23, 35. [Google Scholar] [CrossRef]
  59. Sharma, G.; Mirza, S.; Parshad, R.; Srivastava, A.; Gupta, S.D.; Pandya, P.; Ralhan, R. CpG Hypomethylation of MDR1 Gene in Tumor and Serum of Invasive Ductal Breast Carcinoma Patients. Clin. Biochem. 2010, 43, 373–379. [Google Scholar] [CrossRef]
  60. Kim, H.W.; Park, J.E.; Baek, M.; Kim, H.; Ji, H.W.; Yun, S.H.; Jeong, D.; Ham, J.; Park, S.; Lu, X.; et al. Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer. Cancers 2022, 14, 1232. [Google Scholar] [CrossRef]
  61. Islam, M.S.; Dasgupta, H.; Basu, M.; Roy, A.; Alam, N.; Roychoudhury, S.; Panda, C.K. Reduction of Nuclear Y654-p-Beta-Catenin Expression through SH3GL2-Meditated Downregulation of EGFR in Chemotolerance TNBC: Clinical and Prognostic Importance. J. Cell. Physiol. 2020, 235, 8114–8128. [Google Scholar] [CrossRef]
  62. Treiber, T.; Treiber, N.; Meister, G. Regulation of MicroRNA Biogenesis and Its Crosstalk with Other Cellular Pathways. Nat. Rev. Mol. Cell Biol. 2019, 20, 5–20. [Google Scholar] [CrossRef] [PubMed]
  63. Yu, Z.; Xiao, Q.; Zhao, L.; Ren, J.; Bai, X.; Sun, M.; Wu, H.; Liu, X.; Song, Z.; Yan, Y.; et al. DNA Methyltransferase 1/3a Overexpression in Sporadic Breast Cancer Is Associated with Reduced Expression of Estrogen Receptor-Alpha/Breast Cancer Susceptibility Gene 1 and Poor Prognosis. Mol. Carcinog. 2015, 54, 707–719. [Google Scholar] [CrossRef] [PubMed]
  64. Lee, Y.; Kim, M.; Han, J.; Yeom, K.-H.; Lee, S.; Baek, S.H.; Kim, V.N. MicroRNA Genes Are Transcribed by RNA Polymerase II. EMBO J. 2004, 23, 4051–4060. [Google Scholar] [CrossRef] [PubMed]
  65. Tellier, M.; Maudlin, I.; Murphy, S. Transcription and Splicing: A Two-Way Street. WIREs RNA 2020, 11, e1593. [Google Scholar] [CrossRef]
  66. Calin, G.A.; Dumitru, C.D.; Shimizu, M.; Bichi, R.; Zupo, S.; Noch, E.; Aldler, H.; Rattan, S.; Keating, M.; Rai, K.; et al. Frequent Deletions and Down-Regulation of Micro- RNA Genes MiR15 and MiR16 at 13q14 in Chronic Lymphocytic Leukemia. Proc. Natl. Acad. Sci. USA 2002, 99, 15524–15529. [Google Scholar] [CrossRef]
  67. Le, M.T.N.; Teh, C.; Shyh-Chang, N.; Xie, H.; Zhou, B.; Korzh, V.; Lodish, H.F.; Lim, B. MicroRNA-125b Is a Novel Negative Regulator of P53. Genes Dev. 2009, 23, 862–876. [Google Scholar] [CrossRef]
  68. Chatterjee, B.; Ghosh, K.; Swain, A.; Nalla, K.K.; Ravula, H.; Pan, A.; Kanade, S.R. The Phytochemical Brazilin Suppress DNMT1 Expression by Recruiting P53 to Its Promoter Resulting in the Epigenetic Restoration of P21 in MCF7cells. Phytomedicine 2022, 95, 153885. [Google Scholar] [CrossRef]
  69. Arif, K.M.T.; Elliott, E.K.; Haupt, L.M.; Griffiths, L.R. Regulatory Mechanisms of Epigenetic MiRNA Relationships in Human Cancer and Potential as Therapeutic Targets. Cancers 2020, 12, 2922. [Google Scholar] [CrossRef]
  70. Starlard-Davenport, A.; Kutanzi, K.; Tryndyak, V.; Word, B.; Lyn-Cook, B. Restoration of the Methylation Status of Hypermethylated Gene Promoters by MicroRNA-29b in Human Breast Cancer: A Novel Epigenetic Therapeutic Approach. J. Carcinog. 2013, 12, 15. [Google Scholar] [CrossRef]
  71. Sankrityayan, H.; Kulkarni, Y.A.; Gaikwad, A.B. Diabetic Nephropathy: The Regulatory Interplay between Epigenetics and MicroRNAs. Pharmacol. Res. 2019, 141, 574–585. [Google Scholar] [CrossRef] [PubMed]
  72. Bhardwaj, A.; Singh, H.; Rajapakshe, K.; Tachibana, K.; Ganesan, N.; Pan, Y.; Gunaratne, P.H.; Coarfa, C.; Bedrosian, I. Regulation of MiRNA-29c and Its Downstream Pathways in Preneoplastic Progression of Triple-Negative Breast Cancer. Oncotarget 2017, 8, 19645–19660. [Google Scholar] [CrossRef] [PubMed]
  73. Zeng, X.; Qu, X.; Zhao, C.; Xu, L.; Hou, K.; Liu, Y.; Zhang, N.; Feng, J.; Shi, S.; Zhang, L.; et al. FEN1 Mediates MiR-200a Methylation and Promotes Breast Cancer Cell Growth via MET and EGFR Signaling. FASEB J. 2019, 33, 10717–10730. [Google Scholar] [CrossRef] [PubMed]
  74. Neves, R.; Scheel, C.; Weinhold, S.; Honisch, E.; Iwaniuk, K.M.; Trompeter, H.-I.; Niederacher, D.; Wernet, P.; Santourlidis, S.; Uhrberg, M. Role of DNA Methylation in MiR-200c/141 Cluster Silencing in Invasive Breast Cancer Cells. BMC Res. Notes 2010, 3, 219. [Google Scholar] [CrossRef]
  75. Piperigkou, Z.; Karamanos, N.K. Dynamic Interplay between MiRNAs and the Extracellular Matrix Influences the Tumor Microenvironment. Trends Biochem. Sci. 2019, 44, 1076–1088. [Google Scholar] [CrossRef]
  76. Li, D.; Zhao, Y.; Liu, C.; Chen, X.; Qi, Y.; Jiang, Y.; Zou, C.; Zhang, X.; Liu, S.; Wang, X.; et al. Analysis of MiR-195 and MiR-497 Expression, Regulation and Role in Breast Cancer. Clin. Cancer Res. 2011, 17, 1722–1730. [Google Scholar] [CrossRef]
  77. Tao, S.; Li, H.; Ma, X.; Lian, B.; He, J.; Gao, Y.; Li, J. Methylation-Mediated Silencing of MicroRNA-497 Promotes Breast Cancer Progression Through Up-Regulation of Mucin1. Front. Oncol. 2020, 10, 552099. [Google Scholar] [CrossRef]
  78. Dinami, R.; Buemi, V.; Sestito, R.; Zappone, A.; Ciani, Y.; Mano, M.; Petti, E.; Sacconi, A.; Blandino, G.; Giacca, M.; et al. Epigenetic Silencing of MiR-296 and MiR-512 Ensures HTERT Dependent Apoptosis Protection and Telomere Maintenance in Basal-Type Breast Cancer Cells. Oncotarget 2017, 8, 95674–95691. [Google Scholar] [CrossRef]
  79. Sossey-Alaoui, K.; Downs-Kelly, E.; Das, M.; Izem, L.; Tubbs, R.; Plow, E.F. WAVE3, an Actin Remodeling Protein, Is Regulated by the Metastasis Suppressor MicroRNA, MiR-31, during the Invasion-Metastasis Cascade. Int. J. Cancer J. Int. Cancer 2011, 129, 1331–1343. [Google Scholar] [CrossRef]
  80. Augoff, K.; McCue, B.; Plow, E.F.; Sossey-Alaoui, K. MiR-31 and Its Host Gene LncRNA LOC554202 Are Regulated by Promoter Hypermethylation in Triple-Negative Breast Cancer. Mol. Cancer 2012, 11, 5. [Google Scholar] [CrossRef]
  81. Liu, S.-Y.; Li, X.-Y.; Chen, W.-Q.; Hu, H.; Luo, B.; Shi, Y.-X.; Wu, T.-W.; Li, Y.; Kong, Q.-Z.; Lu, H.-D.; et al. Demethylation of the MIR145 Promoter Suppresses Migration and Invasion in Breast Cancer. Oncotarget 2017, 8, 61731–61741. [Google Scholar] [CrossRef] [PubMed]
  82. Shi, W.; Tang, T.; Li, X.; Deng, S.; Li, R.; Wang, Y.; Wang, Y.; Xia, T.; Zhang, Y.; Zen, K.; et al. Methylation-Mediated Silencing of MiR-133a-3p Promotes Breast Cancer Cell Migration and Stemness via MiR-133a-3p/MAML1/DNMT3A Positive Feedback Loop. J. Exp. Clin. Cancer Res. 2019, 38, 429. [Google Scholar] [CrossRef]
  83. Yu, Y.; Wu, J.; Guan, L.; Qi, L.; Tang, Y.; Ma, B.; Zhan, J.; Wang, Y.; Fang, W.; Zhang, H. Kindlin 2 Promotes Breast Cancer Invasion via Epigenetic Silencing of the MicroRNA200 Gene Family: Kindlin 2 Promotes Breast Cancer Invasion. Int. J. Cancer 2013, 133, 1368–1379. [Google Scholar] [CrossRef] [PubMed]
  84. Ben Gacem, R.; Ben Abdelkrim, O.; Ziadi, S.; Ben Dhiab, M.; Trimeche, M. Methylation of MiR-124a-1, MiR-124a-2, and MiR-124a-3 Genes Correlates with Aggressive and Advanced Breast Cancer Disease. Tumor Biol. 2014, 35, 4047–4056. [Google Scholar] [CrossRef] [PubMed]
  85. Loginov, V.I.; Burdennyy, A.M.; Pronina, I.V.; Khokonova, V.V.; Kurevljov, S.V.; Kazubskaya, T.P.; Kushlinskii, N.E.; Braga, E.A. Novel MiRNA Genes Hypermethylated in Breast Cancer. Mol. Biol. 2016, 50, 705–709. [Google Scholar] [CrossRef]
  86. Loginov, V.; Burdennyy, A.M.; Filippova, E.A.; Pronina, I.; Lukina, S.S.; Kazubskaya, T.P.; Karpukhin, A.; Khodyrev, D.S.; Braga, E.A. Aberrant Methylation of 21 MicroRNA Genes in Breast Cancer: Sets of Genes Associated with Progression and a System of Markers for Predicting Metastasis. Bull. Exp. Biol. Med. 2021, 172, 67–71. [Google Scholar] [CrossRef]
  87. Hasegawa, T.; Adachi, R.; Iwakata, H.; Takeno, T.; Sato, K.; Sakamaki, T. ErbB2 Signaling Epigenetically Suppresses MicroRNA-205 Transcription via Ras/Raf/MEK/ERK Pathway in Breast Cancer. FEBS Open Bio 2017, 7, 1154–1165. [Google Scholar] [CrossRef]
  88. Liu, C.; Li, Y. Hsa_circ_0000078 Regulates MiR-205-5p/EREG Pathway to Inhibit Cervical Cancer Progression. Mol. Biotechnol. 2023. [Google Scholar] [CrossRef]
  89. Lehmann, U.; Hasemeier, B.; Römermann, D.; Müller, M.; Länger, F.; Kreipe, H. Epigenetic inactivation of microRNA genes in mammary carcinoma. Verh. Dtsch. Ges. Pathol. 2007, 91, 214–220. [Google Scholar]
  90. Xu, Q.-L.; Luo, Z.; Zhang, B.; Qin, G.-J.; Zhang, R.-Y.; Kong, X.-Y.; Tang, H.-Y.; Jiang, W. Methylation-Associated Silencing of MiR-9-1 Promotes Nasopharyngeal Carcinoma Progression and Glycolysis via HK2. Cancer Sci. 2021, 112, 4127–4138. [Google Scholar] [CrossRef]
  91. Feng, F.; Liu, H.; Chen, A.; Xia, Q.; Zhao, Y.; Jin, X.; Huang, J. MiR-148-3p and MiR-152-3p Synergistically Regulate Prostate Cancer Progression via Repressing KLF4. J. Cell. Biochem. 2019, 120, 17228–17239. [Google Scholar] [CrossRef] [PubMed]
  92. Yu, S.; Xie, H.; Zhang, J.; Wang, D.; Song, Y.; Zhang, S.; Zheng, S.; Wang, J. MicroRNA-663 Suppresses the Proliferation and Invasion of Colorectal Cancer Cells by Directly Targeting FSCN1. Mol. Med. Rep. 2017, 16, 9707–9714. [Google Scholar] [CrossRef] [PubMed]
  93. Sengupta, D.; Deb, M.; Rath, S.K.; Kar, S.; Parbin, S.; Pradhan, N.; Patra, S.K. DNA Methylation and Not H3K4 Trimethylation Dictates the Expression Status of MiR-152 Gene Which Inhibits Migration of Breast Cancer Cells via DNMT1/CDH1 Loop. Exp. Cell Res. 2016, 346, 176–187. [Google Scholar] [CrossRef] [PubMed]
  94. Xu, Y.; Chao, L.; Wang, J.; Sun, Y. MiRNA-148a Regulates the Expression of the Estrogen Receptor through DNMT1-Mediated DNA Methylation in Breast Cancer Cells. Oncol. Lett. 2017, 14, 4736–4740. [Google Scholar] [CrossRef] [PubMed]
  95. Ng, E.K.O.; Li, R.; Shin, V.Y.; Siu, J.M.; Ma, E.S.K.; Kwong, A. MicroRNA-143 Is Downregulated in Breast Cancer and Regulates DNA Methyltransferases 3A in Breast Cancer Cells. Tumor Biol. 2014, 35, 2591–2598. [Google Scholar] [CrossRef] [PubMed]
  96. Liu, J.; Pang, Y.; Wang, H.; Li, Y.; Sun, X.; Xu, F.; Ren, H.; Liu, D. miR-101 inhibits the proliferation and migration of breast cancer cells via downregulating the expression of DNA methyltransferase 3a. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi Chin. J. Cell. Mol. Immunol. 2016, 32, 299–303. [Google Scholar]
  97. Le, X.-F.; Spizzo, R.; Mao, M.; Wu, Y.; Calin, G.A.; Bast, R.C. Abstract 2051: DNA (Cytosine-5-)-Methyltransferases 3A (DNMT3A) Is a Direct Target of MiR-194 in Breast Cancer. Cancer Res. 2010, 70, 2051. [Google Scholar] [CrossRef]
  98. Noyan, S.; Andac Ozketen, A.; Gurdal, H.; Gur Dedeoglu, B. MiR-770-5p Regulates EMT and Invasion in TNBC Cells by Targeting DNMT3A. Cell. Signal. 2021, 83, 109996. [Google Scholar] [CrossRef]
  99. Aure, M.R.; Fleischer, T.; Bjorklund, S.; Ankill, J.; Castro-Mondragon, J.A.; Borresen-Dale, A.-L.; Tost, J.; Sahlberg, K.K.; Mathelier, A.; Tekpli, X.; et al. Crosstalk between MicroRNA Expression and DNA Methylation Drives the Hormone-Dependent Phenotype of Breast Cancer. Genome Med. 2021, 13, 72. [Google Scholar] [CrossRef]
  100. Li, W.; Yi, J.; Zheng, X.; Liu, S.; Fu, W.; Ren, L.; Li, L.; Hoon, D.S.B.; Wang, J.; Du, G. MiR-29c Plays a Suppressive Role in Breast Cancer by Targeting the TIMP3/STAT1/FOXO1 Pathway. Clin. Epigenetics 2018, 10, 64. [Google Scholar] [CrossRef]
  101. Sandhu, R.; Rivenbark, A.G.; Coleman, W.B. Loss of Post-Transcriptional Regulation of DNMT3b by MicroRNAs: A Possible Molecular Mechanism for the Hypermethylation Defect Observed in a Subset of Breast Cancer Cell Lines. Int. J. Oncol. 2012, 41, 721–732. [Google Scholar] [CrossRef] [PubMed]
  102. Roscigno, G.; Quintavalle, C.; Donnarumma, E.; Puoti, I.; Diaz-Lagares, A.; Iaboni, M.; Fiore, D.; Russo, V.; Todaro, M.; Romano, G.; et al. MiR-221 Promotes Stemness of Breast Cancer Cells by Targeting DNMT3b. Oncotarget 2016, 7, 580–592. [Google Scholar] [CrossRef] [PubMed]
  103. Zmetakova, I.; Kalinkova, L.; Smolkova, B.; Horvathova Kajabova, V.; Cierna, Z.; Danihel, L.; Bohac, M.; Sedlackova, T.; Minarik, G.; Karaba, M.; et al. A Disintegrin and Metalloprotease 23 Hypermethylation Predicts Decreased Disease-Free Survival in Low-Risk Breast Cancer Patients. Cancer Sci. 2019, 110, 1695–1704. [Google Scholar] [CrossRef]
  104. Huisman, C.; van der Wijst, M.G.P.; Schokker, M.; Blancafort, P.; Terpstra, M.M.; Kok, K.; van der Zee, A.G.J.; Schuuring, E.; Wisman, G.B.A.; Rots, M.G. Re-Expression of Selected Epigenetically Silenced Candidate Tumor Suppressor Genes in Cervical Cancer by TET2-Directed Demethylation. Mol. Ther. 2016, 24, 536–547. [Google Scholar] [CrossRef]
  105. Hung, C.-S.; Wang, S.-C.; Yen, Y.-T.; Lee, T.-H.; Wen, W.-C.; Lin, R.-K. Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target. Int. J. Mol. Sci. 2018, 19, 3096. [Google Scholar] [CrossRef] [PubMed]
  106. Bücker, L.; Lehmann, U. CDH1 (E-Cadherin) Gene Methylation in Human Breast Cancer: Critical Appraisal of a Long and Twisted Story. Cancers 2022, 14, 4377. [Google Scholar] [CrossRef] [PubMed]
  107. Lai, J.; Lin, X.; Cao, F.; Mok, H.; Chen, B.; Liao, N. CDKN1C as a Prognostic Biomarker Correlated with Immune Infiltrates and Therapeutic Responses in Breast Cancer Patients. J. Cell. Mol. Med. 2021, 25, 9390–9401. [Google Scholar] [CrossRef]
  108. He, G.-H.; Liu, S.-D.; Shi, X.-Q.; Chen, Y.; Su, L.; Shi, Q.-N.; Sun, C. Rs77283072 Influences Breast Cancer Susceptibility by Regulating CDKN2A Expression. Oncol. Lett. 2023, 25, 1–6. [Google Scholar] [CrossRef]
  109. Sun, X.; Qu, Q.; Lao, Y.; Zhang, M.; Yin, X.; Zhu, H.; Wang, Y.; Yang, J.; Yi, J.; Hao, M. Tumor Suppressor HIC1 Is Synergistically Compromised by Cancer-Associated Fibroblasts and Tumor Cells through the IL-6/PSTAT3 Axis in Breast Cancer. BMC Cancer 2019, 19, 1180. [Google Scholar] [CrossRef]
  110. Aibel, C.; Coll De Peña, A.; Tripathi, A. An Optimized CoBRA Method for the Microfluidic Electrophoresis Detection of Breast Cancer Associated RASSF1 Methylation. BioTech 2023, 12, 7. [Google Scholar] [CrossRef]
  111. Li, P.; Lin, Z.; Liu, Q.; Chen, S.; Gao, X.; Guo, W.; Gong, F.; Wei, J.; Lin, H. Enhancer RNA SLIT2 Inhibits Bone Metastasis of Breast Cancer Through Regulating P38 MAPK/c-Fos Signaling Pathway. Front. Oncol. 2021, 11, 743840. [Google Scholar] [CrossRef] [PubMed]
  112. Liu, S.; Ren, S.; Howell, P.; Fodstad, O.; Riker, A.I. Identification of Novel Epigenetically Modified Genes in Human Melanoma via Promoter Methylation Gene Profiling. Pigment. Cell Melanoma Res. 2008, 21, 545–558. [Google Scholar] [CrossRef] [PubMed]
  113. Wolfsberger, J.; Sakil, H.A.M.; Zhou, L.; van Bree, N.; Baldisseri, E.; de Souza Ferreira, S.; Zubillaga, V.; Stantic, M.; Fritz, N.; Hartman, J.; et al. TAp73 Represses NF-ΚB–Mediated Recruitment of Tumor-Associated Macrophages in Breast Cancer. Proc. Natl. Acad. Sci. USA 2021, 118, e2017089118. [Google Scholar] [CrossRef] [PubMed]
  114. Blasio, A.; Di Fiore, R.; Pratelli, G.; Drago-Ferrante, R.; Saliba, C.; Baldacchino, S.; Grech, G.; Scerri, C.; Vento, R.; Tesoriere, G. A Loop Involving NRF2, MiR-29b-1-5p and AKT, Regulates Cell Fate of MDA-MB-231 Triple-negative Breast Cancer Cells. J. Cell. Physiol. 2020, 235, 629–637. [Google Scholar] [CrossRef] [PubMed]
  115. de Souza Rocha Simonini, P.; Breiling, A.; Gupta, N.; Malekpour, M.; Youns, M.; Omranipour, R.; Malekpour, F.; Volinia, S.; Croce, C.M.; Najmabadi, H.; et al. Epigenetically Deregulated MicroRNA-375 Is Involved in a Positive Feedback Loop with Estrogen Receptor α in Breast Cancer Cells. Cancer Res. 2010, 70, 9175–9184. [Google Scholar] [CrossRef]
  116. Alvarado, S.; Wyglinski, J.; Suderman, M.; Andrews, S.A.; Szyf, M. Methylated DNA Binding Domain Protein 2 (MBD2) Coordinately Silences Gene Expression through Activation of the MicroRNA Hsa-Mir-496 Promoter in Breast Cancer Cell Line. PLoS ONE 2013, 8, e74009. [Google Scholar] [CrossRef]
  117. Lu, J.; Tan, T.; Zhu, L.; Dong, H.; Xian, R. Hypomethylation Causes MIR21 Overexpression in Tumors. Mol. Ther. Oncolytics 2020, 18, 47–57. [Google Scholar] [CrossRef]
  118. Oltra, S.S.; Peña-Chilet, M.; Vidal-Tomas, V.; Flower, K.; Martinez, M.T.; Alonso, E.; Burgues, O.; Lluch, A.; Flanagan, J.M.; Ribas, G. Methylation Deregulation of MiRNA Promoters Identifies MiR124-2 as a Survival Biomarker in Breast Cancer in Very Young Women. Sci. Rep. 2018, 8, 14373. [Google Scholar] [CrossRef]
  119. Kutanzi, K.R.; Yurchenko, O.V.; Beland, F.A.; Checkhun, V.F.; Pogribny, I.P. MicroRNA-Mediated Drug Resistance in Breast Cancer. Clin. Epigenetics 2011, 2, 171–185. [Google Scholar] [CrossRef]
  120. Li, X.; Wu, Y.; Liu, A.; Tang, X. MiR-27b Is Epigenetically Downregulated in Tamoxifen Resistant Breast Cancer Cells Due to Promoter Methylation and Regulates Tamoxifen Sensitivity by Targeting HMGB3. Biochem. Biophys. Res. Commun. 2016, 477, 768–773. [Google Scholar] [CrossRef]
  121. Chen, X.; Lu, P.; Wu, Y.; Wang, D.; Zhou, S.; Yang, S.; Shen, H.-Y.; Zhang, X.; Zhao, J.; Tang, J. MiRNAs-Mediated Cisplatin Resistance in Breast Cancer. Tumor Biol. 2016, 37, 12905–12913. [Google Scholar] [CrossRef]
  122. Manavalan, T.T.; Teng, Y.; Litchfield, L.M.; Muluhngwi, P.; Al-Rayyan, N.; Klinge, C.M. Reduced Expression of MiR-200 Family Members Contributes to Antiestrogen Resistance in LY2 Human Breast Cancer Cells. PLoS ONE 2013, 8, e62334. [Google Scholar] [CrossRef] [PubMed]
  123. He, D.-X.; Gu, X.-T.; Jiang, L.; Jin, J.; Ma, X. A Methylation-Based Regulatory Network for MicroRNA 320a in Chemoresistant Breast Cancer. Mol. Pharmacol. 2014, 86, 536–547. [Google Scholar] [CrossRef] [PubMed]
  124. Wang, Q.; Cheng, Y.; Wang, Y.; Fan, Y.; Li, C.; Zhang, Y.; Wang, Y.; Dong, Q.; Ma, Y.; Teng, Y.; et al. Tamoxifen Reverses Epithelial Mesenchymal Transition by Demethylating MiR-200c in Triple-Negative Breast Cancer Cells. BMC Cancer 2017, 17, 492. [Google Scholar] [CrossRef] [PubMed]
  125. Hu, H.; Li, S.; Cui, X.; Lv, X.; Jiao, Y.; Yu, F.; Yao, H.; Song, E.; Chen, Y.; Wang, M.; et al. The Overexpression of Hypomethylated MiR-663 Induces Chemotherapy Resistance in Human Breast Cancer Cells by Targeting Heparin Sulfate Proteoglycan 2 (HSPG2). J. Biol. Chem. 2013, 288, 10973–10985. [Google Scholar] [CrossRef]
  126. Hu, J.; Yi, T.; Chu, S.; Zeng, H.; Xia, P.; Liu, G.; Chen, G.; Feng, S.; Zhou, H. DNA Methylation of MiR-93: An Important Event in Acquiring Drug Resistance in Breast Cancer Cells. Int. J. Clin. Exp. Med. 2019, 12, 4697–4706. [Google Scholar]
  127. Al-Yozbaki, M.; Jabre, I.; Syed, N.H.; Wilson, C.M. Targeting DNA Methyltransferases in Non-Small-Cell Lung Cancer. Semin. Cancer Biol. 2022, 83, 77–87. [Google Scholar] [CrossRef]
  128. Rupaimoole, R.; Slack, F.J. MicroRNA Therapeutics: Towards a New Era for the Management of Cancer and Other Diseases. Nat. Rev. Drug Discov. 2017, 16, 203–222. [Google Scholar] [CrossRef]
  129. Pang, Y.; Liu, J.; Li, X.; Xiao, G.; Wang, H.; Yang, G.; Li, Y.; Tang, S.-C.; Qin, S.; Du, N.; et al. MYC and DNMT3A-Mediated DNA Methylation Represses MicroRNA-200b in Triple Negative Breast Cancer. J. Cell. Mol. Med. 2018, 22, 6262–6274. [Google Scholar] [CrossRef]
Ijms 24 09360 g001 550
Figure 1. The regulatory mechanisms of miRNA and DNA methylation in breast cancer. A schematic involved in the biogenesis and function of miRNA. Genes of miRNAs are first transcribed by pol II as pri-miRNA. Then, this nascent pri-miRNA is cleaved and shortened by DROSHA and DGCR8 in the nucleus to produce pre-miRNA. The pre-miRNA is transports into the cytoplasm by Exp5, where it is processed, cleaved and modified by RNase III, Dicer/TRBP and AGO2 to generate miRNA duplexes. Finally, the double strand is dissociated into a single strand, and AGO-2 is connected with guide strand to form an RNA-induced silencing complex (miRNA:RISC). In addition, the DNMTs gene undergoes a series of complex processes of transcription and finally forms the mature mRNA. The methylation of miRNAs is usually regulated by DNMTs. In turn, miRNA:RISC pairs with its complimentary target sequence on the 3’-UTR of DNMTs mRNA in a perfect and imperfect manner to suppress the expression level of DNMTs, forming a regulatory loop between miRNA and DNMTs in BC development. Note: The arrows represent the steps involved in the biogenesis and functions of miRNAs.
Figure 1. The regulatory mechanisms of miRNA and DNA methylation in breast cancer. A schematic involved in the biogenesis and function of miRNA. Genes of miRNAs are first transcribed by pol II as pri-miRNA. Then, this nascent pri-miRNA is cleaved and shortened by DROSHA and DGCR8 in the nucleus to produce pre-miRNA. The pre-miRNA is transports into the cytoplasm by Exp5, where it is processed, cleaved and modified by RNase III, Dicer/TRBP and AGO2 to generate miRNA duplexes. Finally, the double strand is dissociated into a single strand, and AGO-2 is connected with guide strand to form an RNA-induced silencing complex (miRNA:RISC). In addition, the DNMTs gene undergoes a series of complex processes of transcription and finally forms the mature mRNA. The methylation of miRNAs is usually regulated by DNMTs. In turn, miRNA:RISC pairs with its complimentary target sequence on the 3’-UTR of DNMTs mRNA in a perfect and imperfect manner to suppress the expression level of DNMTs, forming a regulatory loop between miRNA and DNMTs in BC development. Note: The arrows represent the steps involved in the biogenesis and functions of miRNAs.
Ijms 24 09360 g001
Table
Table 1. Aberrantly hypermethylated genes involved in drug resistance in BC and their function.
Table 1. Aberrantly hypermethylated genes involved in drug resistance in BC and their function.
GenesDrug ResistanceFunctionReference
GFBITrastuzumabEMT[54]
BMP6DoxorubicinEMT[52]
RASSF10DocetaxelCell proliferation[57]
SALL2TamoxifenInduction of ERα and downregulation of PTEN and activation of Akt/mTOR signaling pathway[51]
GCSDoxorubicinUnknown[49]
PAX2OftamoxifenUnknown[55]
ESR1Endocrine, CisplatinUnknown[50,56]
Table
Table 2. Aberrantly hypomethylated genes involved in drug resistance in BC and their function.
Table 2. Aberrantly hypomethylated genes involved in drug resistance in BC and their function.
GenesDrug ResistanceFunctionsReference
SH3GL2Doxorubicin, Epirubicin, 5-flurouracile, CyclophosphamideProliferation[61]
MDR1Multi-DrugTumor size and advanced tumor stage[59]
MMP1TamoxifenApoptosis[60]
LDHBTamoxifenUnknown[58]
Table
Table 3. Epigenetic miRNAs and their functions in breast cancer.
Table 3. Epigenetic miRNAs and their functions in breast cancer.
Epigenetic miRNA in Breast CancerFunctionReference
miR-29cProliferation[72]
miR-200aProliferation[73]
miR-200c/141Invasion[74]
miR-203Invasion[75]
miR-195/497Proliferation, invasion[76,77]
miR-296-5p/-512-5pProliferation, cell apoptosis[78]
miR-31Migration, invasion[79,80]
miR-145Migration, invasion, angiogenesis[81]
miR-133a-3pProliferation, migration, invasion and stemness[82]
miR-200bMigration, invasion, stemness[83]
miR-124a-1/2/3Clinical makers (tumor growth, lymph node metastasis)[84]
miR-1258Clinical makers (lymph nodes or distant organs metastasis)[85,86]
miR-9-3/339Clinical makers (lymph node metastasis, late (III–IV) clinical stages, tumor size)[86]
miR124-1/-34B/-34CClinical maker (late (III–IV) clinical stages)[86]
miR-127Clinical makers (lymph node metastasis, late (III–IV) clinical stages)[86]
miR-132/-137Clinical features (lymph node metastasis, tumor defferentiation, malignancy)[85]
miR-205Unknown[87]
miR-124a3/-148/-152/-9-1/633Unknown[89]
Table
Table 4. The DNMTs targeted by miRNAs and their functions.
Table 4. The DNMTs targeted by miRNAs and their functions.
miRNAsmiRNA Target DNMTsFunctionReference
miR-152DNMT1Migration[93]
miR-148aDNMT1Unknown[94]
miR-143DNMT3AProliferation[95]
miR-101DNMT3AProliferation, migration[96]
miR-194DNMT3ACell cycle[97]
miR-770-5pDNMT3AMigration, invasion (EMT)[98]
miR-29c-5pDNMT3AUnknown[99]
miR-29cDNMT3BProliferation, migration, invasion[100,101]
miR-221DNMT3BStemness[102]
miR-148b/-26b/-29cDNMT3BUnknown[101]
miR-29bDNMT3A, DNMT3BProliferation[70]
miR-29B-1-5pDNMT1, DNMT3A, DNMT3BProliferation[114]
Table
Table 5. Aberrantly hypermethylated miRNAs involved in drug resistance in BC and their functions.
Table 5. Aberrantly hypermethylated miRNAs involved in drug resistance in BC and their functions.
miRNADrug ResistanceFunctionReference
miR-27bTamoxifenInvasion (EMT)[120]
miR-29s/132CisplatinProliferation, migration, invasion[121]
miR-200b/cTamoxifen and FulvestrantProliferation, migration, invasion[122]
miR-320aAdriamycin and PaclitaxelUnknown[123]
Table
Table 6. Aberrantly hypomethylated miRNAs involved in drug resistance in BC and their functions.
Table 6. Aberrantly hypomethylated miRNAs involved in drug resistance in BC and their functions.
miRNADrug ResistanceFunctionReference
miR-200cTamoxifenInvasion (EMT)[124]
miR-663Doxorubicin, Docetaxel and CyclophosphamideProliferation, apoptosis[125]
miR-93DoxorubicinProliferation, apoptosis[126]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ma, L.; Li, C.; Yin, H.; Huang, J.; Yu, S.; Zhao, J.; Tang, Y.; Yu, M.; Lin, J.; Ding, L.; et al. The Mechanism of DNA Methylation and miRNA in Breast Cancer. Int. J. Mol. Sci. 2023, 24, 9360. https://doi.org/10.3390/ijms24119360

AMA Style

Ma L, Li C, Yin H, Huang J, Yu S, Zhao J, Tang Y, Yu M, Lin J, Ding L, et al. The Mechanism of DNA Methylation and miRNA in Breast Cancer. International Journal of Molecular Sciences. 2023; 24(11):9360. https://doi.org/10.3390/ijms24119360

Chicago/Turabian Style

Ma, Lingyuan, Chenyu Li, Hanlin Yin, Jiashu Huang, Shenghao Yu, Jin Zhao, Yongxu Tang, Min Yu, Jie Lin, Lei Ding, and et al. 2023. "The Mechanism of DNA Methylation and miRNA in Breast Cancer" International Journal of Molecular Sciences 24, no. 11: 9360. https://doi.org/10.3390/ijms24119360

APA Style

Ma, L., Li, C., Yin, H., Huang, J., Yu, S., Zhao, J., Tang, Y., Yu, M., Lin, J., Ding, L., & Cui, Q. (2023). The Mechanism of DNA Methylation and miRNA in Breast Cancer. International Journal of Molecular Sciences, 24(11), 9360. https://doi.org/10.3390/ijms24119360

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop