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乳腺癌是全世界女性最常见的恶性肿瘤，基因突变和表观遗传改变导致治疗耐药、复发和转移。DNA甲基化修饰作为常见的表观遗传学修饰，通过动态调控基因表达参与乳腺癌的发生、发展及化疗耐药。本文综述了DNA甲基化与去甲基化在乳腺癌中的调控作用，揭示其通过影响肿瘤增殖、转移、代谢重编程及免疫逃逸等恶性表型促进疾病进展。同时，异常的DNA甲基化可导致抑癌基因沉默或促癌基因激活，进而介导乳腺癌对化疗药物的耐药性。DNA甲基转移酶（DNA methyltransferases,DNMT）抑制剂可通过去甲基化作用激活沉默的基因，增强化疗敏感性，且与其他药物联合使用展现出协同抗肿瘤潜力。此外，本文探讨了个体化治疗的应用前景，并提出未来需进一步探索乳腺癌亚型特异性甲基化标志物及优化联合治疗方案，以克服耐药性并提高疗效，为乳腺癌的精准治疗提供新的表观遗传学策略。
Abstract：Breast cancer is the most common malignant tumor in women worldwide. Gene mutations and epigenetic changes lead to treatment resistance, recurrence and metastasis. As a common epigenetic modification, DNA methylation modification is involved in the occurrence, development and chemotherapy resistance of breast cancer by dynamically regulating gene expression. This article reviews the regulatory role of DNA methylation and demethylation in breast cancer, and reveals that it promotes disease progression by affecting malignant phenotypes such as tumor proliferation, metastasis, metabolic reprogramming, and immune escape. At the same time, abnormal DNA methylation can lead to silencing of tumor suppressor genes or activation of oncogenes, and mediates the resistance of breast cancer to chemotherapeutic drugs. DNA methyltransferase(DNMT) inhibitors can activate silent genes through demethylation, enhance chemotherapy sensitivity, and show synergistic anti-tumor potential in combination with other drugs. In addition, this paper discusses the application prospect of individualized treatment, and proposes that in the future, it is necessary to further explore subtype-specific methylation markers of breast cancer and optimize the combined treatment plan to overcome drug resistance and improve the efficacy, so as to provide a new epigenetic strategy for the precise treatment of breast cancer.
[1]Bray F,Laversanne M,Sung H,et al. Global cancer statistics 2022:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin,2024,74(3):229-263.
[2]中国抗癌协会乳腺癌专业委员会.中国乳腺癌筛查与早期诊断指南[J].中国癌症杂志，2022,32(4):363-372.
[3]Dowling G P,Daly G R,Hegarty A,et al. Neoadjuvant HER2 inhibition induces ESR1 DNA methylation alterations resulting in clinically relevant ER expression changes in breast cancers[J]. Cancer Commun(Lond),2025,45(2):198-202.
[4]Holliday R. Epigenetics:an overview[J]. Dev Genet,1994,15(6):453-457.
[5]Jones P A,Takai D. The role of DNA methylation in mammalian epigenetics[J]. Science,2001,293(5532):1068-1070.
[6]Newell-Price J,Clark A J,King P. DNA methylation and silencing of gene expression[J]. Trends Endocrinol Metab,2000,11(4):142-148.
[7]Tahiliani M,Koh K P,Shen Y,et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1[J]. Science,2009,324(5929):930-935.
[8]Vietri M T,D'Elia G,Benincasa G,et al. DNA methylation and breast cancer:a way forward(Review)[J]. Int J Oncol,2021,59(5):98.
[9]Han B,Zheng R,Zeng H,et al. Cancer incidence and mortality in China,2022[J]. J Natl Cancer Cent,2024,4(1):47-53.
[10]Dawson M A,Kouzarides T. Cancer epigenetics:from mechanism to therapy[J]. Cell,2012,150(1):12-27.
[11]Stefansson O A,Moran S,Gomez A,et al. A DNA methylation-based definition of biologically distinct breast cancer subtypes[J]. Mol Oncol,2015,9(3):555-568.
[12]赵琳，于兆进，何苗，等.三阴性乳腺癌中DNMT1表达与ERα基因启动子甲基化的关系[J].现代肿瘤医学，2016,24(9):1376-1379.
[13]Liu X Y,Ma D,Xu X E,et al. Genomic landscape and endocrine-resistant subgroup in estrogen receptor-positive,progesterone receptor-negative,and HER2-negative breast cancer[J]. Theranostics,2018,8(22):6386-6399.
[14]金姝，朱琪，朱元，等.乳腺癌组织及癌旁组织HER2基因CpG岛甲基化水平及其mRNA表达的研究[J].检验医学，2020,35(5):481-486.
[15]He J,Wu M,Xiong L,et al. BTB/POZ zinc finger protein ZBTB16 inhibits breast cancer proliferation and metastasis through upregulating ZBTB28 and antagonizing BCL6/ZBTB27[J]. Clin Epigenetics,2020,12(1):82.
[16]Zeng X,Qu X,Zhao C,et al. FEN1 mediates miR-200a methylation and promotes breast cancer cell growth via MET and EGFR signaling[J]. FASEB J,2019,33(10):10717-10730.
[17]Li T,Zhai D,Zhang M,et al. KIF17 maintains the epithelial phenotype of breast cancer cells and curbs tumour metastasis[J]. Cancer Lett,2022,548:215904.
[18]Lian B,Li H,Liu Y,et al. Expression and promoter methylation status of OPCML andits functions in the inhibition ofcell proliferation,migration,and invasion in breast cancer[J]. Breast Cancer,2021,28(2):448-458.
[19]Zhang H,Gao M,Zhao W,et al. The chromatin architectural regulator SND1 mediates metastasis in triple-negative breast cancer by promoting CDH1 gene methylation[J]. Breast Cancer Res,2023,25(1):129.
[20]Li Z,Wang P,Cui W,et al. Tumour-associated macrophages enhance breast cancer malignancy via inducing ZEB1-mediated DNMT1 transcriptional activation[J].Cell Biosci,2022,12(1):176.
[21]Li D,Zhao W,Zhang X,et al. NEFM DNA methylation correlates with immune infiltration and survival in breast cancer[J]. Clin Epigenetics,2021,13(1):112.
[22]Cheng G,Fan X,Hao M,et al. Higher levels of TIMP-1expression are associated with a poor prognosis in triplenegative breast cancer[J]. Mol Cancer, 2016,15(1):30.
[23]Liang H,Zhou G,Lv L,et al. KRAS expression is a prognostic indicator and associated with immune infiltration in breast cancer[J]. Breast Cancer,2021,28(2):379-386.
[24]Liao R,Chen X,Cao Q,et al. AMD1 promotes breast cancer aggressiveness via a spermidine-eIF5A hypusination-TCF4 axis[J]. Breast Cancer Res,2024,26(1):70.
[25]Chen N,Zhao G,Yan X,et al. A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1[J]. Genome Biol,2018,19(1):218.
[26]国家卫生健康委员会医政医管局.乳腺癌诊疗指南（2022年版）[J].中国综合临床，2024(01):1-30.
[27]Pedersen C A,Cao M D,Fleischer T,et al. DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival[J]. Breast Cancer Res,2022,24(1):43.
[28]Yao S,Hu Q,Kerns S,et al. Impact of chemotherapy for breast cancer on leukocyte DNA methylation landscape and cognitive function:a prospective study[J]. Clin Epigenetics,2019,11(1):45.
[29]Romero-Garcia S,Prado-Garcia H,Carlos-Reyes A.Role of DNA methylation in the resistance to therapy in solid tumors[J]. Front Oncol,2020,10:1152.
[30]Xiong Z,Yang L,Li N,et al. DAB2IP attenuates chemoresistance of triple-negative breast cancer through sequestration of RAC1 to prevent β-catenin nuclear accumulation[J]. Clin Transl Med,2022,12(12):e1133.
[31]Vanklompenberg M K,Bedalov C O,Soto K F,et al.APC selectively mediates response to chemotherapeutic agents in breast cancer[J]. BMC Cancer,2015,15:457.
[32]Bin Y,Ding Y,Xiao W,et al. RASSF1A:a promising target for the diagnosis and treatment of cancer[J]. Clin Chim Acta,2020,504:98-108.
[33]Jahangiri R,Mosaffa F,Emami Razavi A,et al. PAX2promoter methylation and AIB1 overexpression promote tamoxifen resistance in breast carcinoma patients[J]. J Oncol Pharm Pract,2022,28(2):310-325.
[34]Wargon V,Fernandez S V,Goin M,et al. Hypermethylation of the progesterone receptor A in constitutive antiprogestin-resistant mouse mammary carcinomas[J].Breast Cancer Res Treat,2011,126(2):319-332.
[35]Palomeras S,Diaz-Lagaresá，Vi?As G,et al. Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer[J]. Breast Cancer Res,2019,21(1):79.
[36]Zhang J,Zhang F,Zhang F,et al. Correlation between promoter methylation of the LDH-C4 gene and DNMT expression in breast cancer and their prognostic significance[J]. Oncol Lett,2022,23(1):35.
[37]Rossi V,Govoni M,Farabegoli F,et al. Lactate is a potential promoter of tamoxifen resistance in MCF7 cells[J]. Biochim Biophys Acta Gen Subj,2022,1866(9):130185.
[38]Zheng D,Fu W,Jin L,et al. The overexpression and clinical significance of AP1S1 in breast cancer[J]. Cancer Manag Res,2022,14:1475-1492.
[39]李晨欣，李启基，张娣，等. AP1S1在乳腺癌中的表达及其对化疗耐药的影响[J].热带医学杂志，2024,24(6):776-782.
[40]Zappe K,Cichna-Markl M. Aberrant DNA methylation of ABC transporters in cancer[J]. Cells,2020,9(10):2281.
[41]中国抗癌协会乳腺癌专业委员会，中华医学会肿瘤学分会乳腺肿瘤学组，邵志敏.中国抗癌协会乳腺癌诊治指南与规范（2024年版）[J].中国癌症杂志，2023,33(12):1092-1186.
[42]杨彩云，李国超，宋丹，等. DNA甲基化/去甲基化的相关药物治疗研究现状与展望[J].生命科学，2018,30(4):383-390.
[43]Lyko F,Brown R. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies[J]. J Natl Cancer Inst,2005,97(20):1498-1506.
[44]Kantarjian H,Borthakur G,Daver N,et al. Current status and research directions in acute myeloid leukemia[J]. Blood Cancer J,2024,14(1):163.
[45]Zanotta S,Galati D,De Filippi R,et al. Breakthrough in blastic plasmacytoid dendritic cell neoplasm cancer therapy owing to precision targeting of CD123[J]. Int J Mol Sci,2024,25(3):1454.
[46]Connolly R M,Li H,Jankowitz R C,et al. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat:a phase II national cancer institute/stand up to cancer study[J]. Clin Cancer Res,2017,23(11):2691-2701.
[47]Dahn M L,Cruickshank B M,Jackson A J,et al.Decitabine response in breast cancer requires efficient drug processing and is not limited by multidrug resistance[J]. Mol Cancer Ther,2020,19(5):1110-1122.
[48]Chen M,Shabashvili D,Nawab A,et al. DNA methyltransferase inhibitor,zebularine,delays tumor growth and induces apoptosis in a genetically engineered mouse model of breast cancer[J]. Mol Cancer Ther,2012,11(2):370-382.
[49]Zhang J,Zheng Y G. SAM/SAH analogs as versatile tools for SAM-dependent methyltransferases[J]. ACS Chem Biol,2016,11(3):583-597.
[50]Schumann N A B,Mendon?A A S,Silveira M M,et al.Procaine and S-adenosyl-l-homocysteine affect the expression of genes related to the epigenetic machinery and change the DNA methylation status of in vitro cultured bovine skin fibroblasts[J]. DNA Cell Biol,2020,39(1):37-49.
[51]Liu F,Zhou H,Peng Y,et al. Plasma one-carbon metabolism-related micronutrients and the risk of breast cancer:involvement of DNA methylation[J]. Nutrients,2023,15(16):3621.
[52]Lee B H,Yegnasubramanian S,Lin X,et al. Procainamide is a specific inhibitor of DNA methyltransferase 1[J]. J Biol Chem,2005,280(49):40749-40756.
[53]Villar-Garea A,Fraga M F,Espada J,et al. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells[J]. Cancer Res,2003,63(16):4984-4989.
[54]Fang M Z, Wang Y, Ai N, et al. Tea polyphenol(-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines[J]. Cancer Res, 2003, 63(22):7563-70.
[55]Sheng J,Shi W,Guo H,et al. The inhibitory effect of(-)-epigallocatechin-3-gallate on breast cancer progression via reducing SCUBE2 methylation and DNMT activity[J]. Molecules,2019,24(16):2899.
[56]Zambrano P,Segura-Pacheco B,Perez-Cardenas E,et al. A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes[J].BMC Cancer,2005,5:44.
[57]Andrade F O,Nguyen N M,Warri A,et al. Reversal of increased mammary tumorigenesis by valproic acid and hydralazine in offspring of dams fed high fat diet during pregnancy[J]. Sci Rep,2019,9(1):20271.
[58]Plummer R,Vidal L,Griffin M,et al. Phase I study of MG98,an oligonucleotide antisense inhibitor of human DNA methyltransferase 1,given as a 7-day infusion in patients with advanced solid tumors[J]. Clin Cancer Res,2009,15(9):3177-3183.
[59]Mahmood N,Arakelian A,Cheishvili D,et al. S-adenosylmethionine in combination with decitabine shows enhanced anti-cancer effects in repressing breast cancer growth and metastasis[J]. J Cell Mol Med,2020,24(18):10322-10337.
[60]Buocikova V,Longhin E M,Pilalis E,et al. Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models[J]. Biomedecine Pharmacother,2022,147:112662.
[61]Nakajima W,Miyazaki K,Sakaguchi M,et al. Epigenetic priming with decitabine augments the therapeutic effect of cisplatin on triple-negative breast cancer cells through induction of proapoptotic factor NOXA[J]. Cancers,2022,14(1):248.
[62]尹婉宜，刘清池，董雯，等.补肾生血中药联合超低剂量地西他滨治疗高危MDS疗效观察[C]. 2019年中国中西医结合学会血液病专业委员会学术年会暨浙江省中西医结合学会血液病专业委员会学术年会，2019:6.
[63]Valdez B C,Tsimberidou A M,Yuan B,et al. Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells:Implications for novel therapy[J]. Oncotarget,2024,15:361-373.
基本信息:
中图分类号:R737.9
引用信息:
[1]黄强,王宇煊,黄盼盼.DNA甲基化修饰在乳腺癌中的研究进展[J].赣南医科大学学报().
基金信息:
国家自然科学基金青年科学基金项目(82202928)
2026-07-08
2026-07-08
2026-07-08