Breast cancer decitabine

Kinesin superfamily motor protein 17 (KIF17) was previously identified downregulated in breast cancer and correlated with patient prognosis. However, its pathophysiological role in tumours remains unknown. Here, we confirmed that KIF17 was significantly under-expressed in breast cancer tissues and low KIF17 expression correlated with poor outcomes in patients with breast cancer. In vitro and in vivo experiments demonstrated that KIF17 overexpression in breast cancer cell lines significantly inhibited breast cancer invasion and metastasis...

PURPOSE: To understand pyroptosis induced by ionizing radiation and its implications for radiotherapy, we explored the involved factors, possible mechanisms of radiation-induced pyroptosis and consequent antitumor immunity. METHODS AND MATERIALS: The occurrence of pyroptosis was assessed by cell morphology, lactate dehydrogenase (LDH) release, Annexin V/PI staining and the cleavage of GSDME. Cell radiosensitivity was tested with MTT and colony survival assays. Xenograft tumor volume, Ki-67, CD8+ lymphocytes and ELISA were used to evaluate the effect of GSDME on tumor suppression after irradiation...

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ERβ agonist DPN on ERα and ERβ re-expressions in the MDA-MB-231 cells as a model of TNBC...

Background: Active breast cancer-associated fibroblasts (CAFs) play a leading role in breast carcinogenesis through promoting angiogenesis and resistance to therapy. Consequently, these active stromal cells have significant influence on patient outcome. Therefore, we explored here the role of the DNA methyltransferase 1 (DNMT1) protein in CAF-dependent promotion of angiogenesis as well as the prognostic power of DNMT1 level in both cancer cells and their adjacent CAFs in locally advanced breast cancer patients...

Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression by controlling the chromatin structure and accessibility to transcription factors. Cancer cells have their own transcriptional programs, and we sought to alter such a cancer-specific program by enforcing expression of the catalytic domain (CD) of the methylcytosine dioxygenase TET2 in breast cancer cells. The TET2 CD decreased the tumorigenic potential of cancer cells through both activation and repression of a repertoire of genes that, interestingly, differed in part from the one observed upon treatment with the hypomethylating agent decitabine...

PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression. Inhibition of DNA methyltransferases (DNMTs) leads to elevated hyaluronan levels; however, whether DNMT inhibitors control PH20 remains unclear. Here, we report that the DNMT1 inhibitor, decitabine, suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1 (PAS1). PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone methyltransferase SUV39H1...

Acquired drug resistance and metastasis in breast cancer (BC) are coupled with epigenetic deregulation of gene expression. Epigenetic drugs, aiming to reverse these aberrant transcriptional patterns and sensitize cancer cells to other therapies, provide a new treatment strategy for drug-resistant tumors. Here we investigated the ability of DNA methyltransferase (DNMT) inhibitor decitabine (DAC) to increase the sensitivity of BC cells to anthracycline antibiotic doxorubicin (DOX). Three cell lines representing different molecular BC subtypes, JIMT-1, MDA-MB-231 and T-47D, were used to evaluate the synergy of sequential DAC + DOX treatment in vitro...

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type...

BACKGROUND: DNA methylation plays a crucial role in multiple cellular processes such as gene regulation, chromatin stability, and genetic imprinting. In mammals, DNA methylation is achieved by DNA methyltransferases (DNMTs). A number of studies have associated alterations in DNMT activity to tumorigenesis; however, the exact role of DNMTs in shaping the genome in triple negative breast cancer (TNBC) is still being unraveled. METHODS: In the current study, we employed two DNMT inhibitors (Decitabine and 5-Azacytidine), two TNBC models (MDA-MB-231 and BT-549) and whole transcriptome RNA-Seq and characterized the transcriptional alterations associated with DNMT inhibition...

Active cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment, which promote carcinogenesis and modulate response to therapy. Therefore, targeting these cells or reducing their paracrine pro-carcinogenic effects could be of great therapeutic value. To this end, we sought to investigate the effect of eugenol, a natural phenolic molecule, on active breast CAFs. We have shown that decitabine (5-Aza-2'-deoxycytidine, DAC) and eugenol inhibit the expression of the DNA methyltransferase genes DNMT1 and DNMT3A at both the protein and mRNA levels in breast CAF cells...

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear. METHODS: Using our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC...

BACKGROUND AND PURPOSE: Since DNA methyltransferase enzymes play a key role in DNA methylation, they can be used as a target to alter epigenetic changes and treat cancer. Recent studies have shown that olsalazine, through its potent inhibitory effect on the DNA methyltransferase enzyme, can be a good option. The aim of this study was to investigate the effects of olsalazine on cell viability and expression of CDH1 and uPA genes in MDA-MB-231 cells compared with decitabine. EXPERIMENTAL APPROACH: The cytotoxicity of the drugs was determined using a standard MTT assay...

Despite the concerning adverse effects on tumour development, epigenetic drugs are very promising in cancer treatment. The aim of this study was to compare the differential effects of standard chemotherapy regimens (FEC: 5-fluorouracil plus epirubicine plus cyclophosphamide) in combination with epigenetic modulators (decitabine, valproic acid): (a) on gene methylation levels of selected tumour biomarkers (LINE-1, uPA, PAI-1, DAPK); (b) their expression status (uPA and PAI-1); (c) differentiation status (5meC and H3K27me3)...

Aim: The methylation and expression levels of USP44 in breast cancer were investigated and their effects on tumor cells were researched. Materials & methods: Bioinformatics was employed to identify the target gene from TCGA database. Sodium bisulfite and decitabine were used for DNA modification and demethylation, and methylation-specific PCR and reverse transcriptase PCR were performed to assess USP44 methylation and expression levels. Tumor cell behaviors were assayed via several in vitro experiments...

DNA methylation is implicated in the acquisition of malignant phenotypes, and the use of epigenetic modulating drugs is a promising anti-cancer therapeutic strategy. 5-aza-2'deoxycytidine (decitabine, 5-azadC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor with proven effectiveness against hematological malignancies and more recently triple-negative breast cancer (BC). Herein, genetic or pharmacological studies uncovered a hitherto unknown feedforward molecular link between DNMT1 and the estrogen related receptor α (ERRα), a key transcriptional regulator of cellular metabolism...

Lysine-specific demethylase 5B (KDM5B/PLU1/JARID1B) is found to be overexpressed in numerous malignancies, including breast, lung, skin, liver, and prostate cancer. Identification of molecules targeting the KDM5B enzyme could be a potential lead in cancer research. Although many KDM5B inhibitors with promising outcomes have been developed so far, its further application in clinical practice is limited due to toxicity and lack of target specificity. Here, we summarize the significance of targeting KDM5B in anticancer therapy and report the molecular docking studies of some known anti-viral agents, decitabine, entecavir, abacavir, penciclovir, and 3-deazaneplanocin A in the catalytic domain JmjC of KDM5B...

Abnormal DNA methylation orchestrates many of the cancer-related gene expression irregularities such as the inactivation of tumour suppressor genes through hypermethylation as well as activation of prometastatic genes through hypomethylation. The fact that DNA methylation abnormalities can be chemically reversed positions the DNA methylation machinery as an attractive target for anti-cancer drug development. However, although in vitro studies suggested that targeting concordantly hypo- and hypermethylation is of benefit in suppressing both oncogenic and prometastatic functions of breast cancer cells, this has never been tested in a therapeutic setting in vivo...

Immunotherapy shows remarkable efficacy in treating several types of cancer such as melanoma, leukemia, and lung carcinoma, but its therapeutic effect for most solid tumors is still limited. Various cancer therapies, such as chemotherapy, radiotherapy and phototherapy, kill solid tumors through non-inflammatory apoptosis or ablation, rather than making solid tumors immunogenic. As a highly-inflammatory programmed cell death (PCD), pyroptosis provides a great opportunity to alleviate immunosuppression and promote a systemic immune response in treating solid tumors...

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...

Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBCs) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype-specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells...