期刊
SEMINARS IN CANCER BIOLOGY
卷 72, 期 -, 页码 198-213出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.semcancer.2020.05.010
关键词
DNMT1; Methylation; Triple-negative breast cancer; Epithelial-mesenchymal transition; Inhibitors
类别
资金
- Bridging Grant, Universiti Sains Malaysia [304.PPSP.6316332]
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with DNMT1 playing a crucial role in promoting tumorigenesis through multiple mechanisms. DNMT1 inhibitors show promise in targeting TNBC cells and sensitizing patients to immune checkpoint blockade therapy. This highlights the potential of DNMT1 as a therapeutic target for TNBC, aiming to disrupt its metastatic and aggressive phenotypes.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Altered epigenetics regulation including DNA hypermethylation by DNA methyltransferase 1 (DNMT1) has been implicated as one of the causes of TNBC tumorigenesis. In this review, the oncogenic functions rendered by DNMT1 in TNBCs, and DNMT1 inhibitors targeting TNBC cells are presented and discussed. In summary, DNMT1 expression is associated with poor breast cancer survival, and it is overexpressed in TNBC subtype. The oncogenic roles of DNMT1 in TNBCs include: (1) Repression of estrogen receptor (ER) expression; (2) Promotion of epithelial-mesenchymal transition (EMT) required for metastasis; (3) Induces cellular autophagy and; (4) Promotes the growth of cancer stem cells in TNBCs. DNMT1 confers these phenotypes by hypermethylating the promoter regions of ER, multiple tumor suppressor genes, microRNAs and epithelial markers involved in suppressing EMT. DNMT1 inhibitors exert anti-tumorigenic effects against TNBC cells. This includes the hypomethylating agents azacitidine, decitabine and guadecitabine that might sensitize TNBC patients to immune checkpoint blockade therapy. DNMT1 represents an epigenetic target for TNBC cells destruction as well as to derail their metastatic and aggressive phenotypes.
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