Identification of a three-gene signature in the triple-negative breast cancer

Wang, Liping; Luo, Zhongyang; Sun, Mengyao; Yuan, Qiuyue; Zou, Yinggang; Fu, Deyuan

doi:10.32604/biocell.2022.017337

Cited by 3 publications

(3 citation statements)

References 29 publications

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“…Most of the basal-like breast tumors are triple-negative (lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER2) (Rody et al, 2011). Histologically, basal-like tumors are usually high grade, with high mitotic indices, pushing borders of invasion, and atypical medullary features (Milioli et al, 2017;Wang et al, 2022). These features make them highly aggressive, with limited therapeutic responses.…”

Section: Discussionmentioning

confidence: 99%

Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer

Tuo¹,

LIU²

2023

Biocell

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Retinoic acid receptor responder 3 (RARRES3) has been characterized as a tumor suppressor in multiple types of cancer. This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast cancer. The DNA methylation status of RARRES3 was checked in the basal-like subtype, and the underlying mechanisms of its dysregulation were explored. RNA-sequencing (seq) and methylation data from The Cancer Genome Atlas were used for in-silico analysis. Basal-like representative SUM149 and MDA-MB-468 cell lines were used for in vitro and in vivo studies.Compared to tumor-adjacent normal tissues, only the basal-like tumor tissues had significantly downregulated RARRES3 expression. The methylation level of four CpG sites in the promoter region showed a strong negative correlation with RARRES3 expression. The gene coding for DNA methyltransferase 3A (DNMT3A) had consistent positive correlations with the methylation of the CpG sites. Chromatin Immunoprecipitation-quantitative polymerase chain-reaction and bisulfite sequencing PCR showed that DNMT3A could bind to the promoter region of RARRES3 and promote methylation of the CpG sites within the region. DNMT3A knockdown significantly restored RARRES3 expression at the mRNA and protein level in the two cell lines. CCK-8, colony formation, and flow cytometric analysis showed that RARRES3 overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the DNMT3A overexpression-induced activation of ERK1/2 and PI3K/AKT signaling. In summary, this study revealed that DNMT3A enhances promoter methylation of the RARRES3 gene and suppresses its transcription in basal-like breast cancer. The DNMT3A-RARRES3 signaling pathway might be a potential target for the treatment of this tumor subtype.

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Section: Discussionmentioning

confidence: 99%

Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer

Tuo¹,

LIU²

2023

Biocell

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“…The interaction between tumors and TME has been a hot topic in recent years ( 3 , 28 – 30 ). On the one hand, TME plays a role in immune surveillance and immune defense of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T-cells-related signature for identifying a prognostic subtype of hepatocellular carcinoma with an exhausted tumor microenvironment

Zhang

2022

Front. Immunol.

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Regulatory T-Cells (Tregs) are important in the progression of hepatocellular cancer (HCC). The goal of this work was to look into Tregs-related genes and develop a Tregs-related prognostic model. We used the weighted gene coexpression network analysis (WGCNA) to look for Tregs-related genes in the TCGA, ICGC, and GSE14520 cohorts and then used the non-negative matrix factorization (NMF) algorithm to find Tregs-related subpopulations. The LASSO-Cox regression approach was used to determine Tregs-related genes, which were then condensed into a risk score. A total of 153 overlapping genes among the three cohorts were considered Tregs-related genes. Based on these genes, two Tregs-associated clusters that varied in both prognostic and biological characteristics were identified. When compared with Cluster 1, Cluster 2 was a TME-exhausted HCC subpopulation with substantial immune cell infiltration but a poor prognosis. Five Tregs-related genes including HMOX1, MMP9, CTSC, SDC3, and TNFRSF11B were finally used to construct a prognostic model, which could accurately predict the prognosis of HCC patients in the three datasets. Patients in the high-risk scores group with bad survival outcomes were replete with immune/inflammatory responses, but exhausted T cells and elevated PD-1 and PD-L1 expression. The results of qRT-PCR and immunohistochemical staining (IHC) analysis in clinical tissue samples confirmed the above findings. Moreover, the signature also accurately predicted anti-PD-L1 antibody responses in the IMvigor210 dataset. Finally, HMOX1, MMP9, and TNFRSF11B were expressed differently in Hep3B and Huh7 cells after being treated with a PD1/PD-L1 inhibitor. In conclusion, our study uncovered a Tregs-related prognostic model that could identify TMEexhausted subpopulations and revealed that PD1/PD-L1 inhibitors could alter the expression levels of HMOX1, MMP9, and TNFRSF11B in Hep3B and Huh7 cells, which might help us better understand Tregs infiltration and develop personalized immunotherapy treatments for HCC patients.

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“…However, breast cancer is a group of heterogeneous tumors with distinct clinical and genomic characteristics (Liu et al, 2022;Nielsen et al, 2014;Wang et al, 2022). A 50-gene quantitative polymerase chain reaction (qPCR assay; Prediction Analysis of Microarray 50, PAM50) of gene profiles can generally classify breast cancer into luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, basal-like (largely triple-negative), and normal-like breast cancer subtypes (Nielsen et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

ENST00000535926 is an unfavorable prognosis-related and tumor-promoting transcript of the CHPF gene in luminal A and B breast cancer

HE¹,

Yong²,

YI³

2023

Biocell

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Chondroitin sulfate synthase 2 (CHPF) is characterized as an oncogenic and poor prognosis-related gene in breast cancer. However, this gene has alternative splicing products encoding proteins of different lengths. Breast cancer is a group of heterogeneous tumors with distinct clinical and genomic characteristics. In this study, we explored the expression profile and prognostic value of the two transcripts of CHPF using data from The Cancer Genome Atlas (TCGA)-BRCA. The functional regulation of the two transcripts was also studied in MCF-7 and BT-474 cells. Among the two transcripts of CHPF, ENST00000535926 expression was significantly upregulated in the tumor samples and was the dominant isoform. ENST00000535926, but not ENST00000243776 upregulation, was associated with significantly worse progression-free survival (PFS) and disease-specific survival (DSS) in luminal A/B cases. However, no significant association was observed in PFS or DSS in other Prediction Analysis of Microarray 50 (PAM50) subgroups. CHPF isoform 2 protein (encoded by ENST00000535926) significantly elevated the expression of P3H1 and RCN3 at the mRNA and protein levels in MCF-7 and BT-474 cells. The effect of ENST00000535926 was significantly stronger than ENST00000243776 in promoting tumor cell colony formation. The expression of P3H1 and RCN3 was negatively correlated with CD8+ T cell infiltration but was positively correlated with cancer-associated fibroblast infiltration in luminal A/B tumors. In summary, this study revealed that ENST00000535926 is an unfavorable prognosis-related and tumor-promoting transcript of the CHPF gene in luminal A/B breast cancer.

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Identification of a three-gene signature in the triple-negative breast cancer

Cited by 3 publications

References 29 publications

Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer

Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer

Regulatory T-cells-related signature for identifying a prognostic subtype of hepatocellular carcinoma with an exhausted tumor microenvironment

ENST00000535926 is an unfavorable prognosis-related and tumor-promoting transcript of the CHPF gene in luminal A and B breast cancer

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