Promoter Methylation Status of the Retinoic Acid Receptor-Beta 2 Gene in Breast Cancer Patients: A Case Control Study and Systematic Review

Yari, Kheirollah; Rahimi, Zohreh

doi:10.1159/000489874

Cited by 12 publications

(10 citation statements)

References 43 publications

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“…It has been widely demonstrated the diminished of RARB mRNA due to epigenetic alterations in BC. It has been proposed as an epigenetic marker for BC diagnosis [25,43,44]. The role of RARγ has not been extensively studied in the context of BC.…”

Section: Discussionmentioning

confidence: 99%

Combination Treatment of Retinoic Acid Plus Focal Adhesion Kinase Inhibitor Prevents Tumor Growth and Breast Cancer Cells Metastasis

Castro

Mondaca

Fernandez-Muñoz

et al. 2021

Preprint

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All-trans retinoic acid (RA) is the primary metabolite of vitamin A and controls the development and homeostasis of organisms and tissues. RA and its natural and synthetic derivatives, known as retinoids, are promising agents in treating and chemoprevention different neoplasias, including breast cancer (BC). Focal adhesion kinase (FAK) is a crucial regulator of cell migration, and its overexpression is associated with the metastatic behavior of tumors. Thus, pharmaceutical FAK inhibitors (FAKi) have been developed to counter its action. In this work, we hypothesize that RA plus FAKi (RA+FAKi) approach could improve inhibition of tumor progression. By in silico analysis, we confirmed RARA, SRC, and PTK2 (encoding RARα, Src, and FAK, respectively) overexpression in all breast cells tested. In metastatic BC cells, we reveal that genes encoding proteins that FAK directly or indirectly modulates are deregulated compared to normal cells. We showed a different pattern of genes up/down-regulated between RA-resistant and RA-sensitive BC cells. In addition, we demonstrated that both RA-resistant BC cells (MDA-MB-231 and MDA-MB-468) display the same behavior after RA treatment, modulating the expression of genes involved in Src-FAK signaling. Furthermore, we demonstrated that although RA and FAKi administered separately decrease viability, adhesion, and migration in mammary adenocarcinoma LM3 cells, their combination exerts a higher effect. We also evidenced that RA effects are extrapolated to other cancer cells, including the human cervical carcinoma cells HeLa. In an orthotopic assay of LM3 tumor growth, RA and FAKi administered separately reduce tumor growth; however, the combined treatment induces the more potent inhibition increasing mice survival. Moreover, in an experimental metastatic assay, RA significantly reduces metastatic lung dissemination of LM3 cells. Overall, these results indicate that RA resistance would reflect deregulation of most RA-target genes, including genes encoding components of the Src-FAK pathway. Our study demonstrates that RA plays an essential role in disrupting BC tumor growth and metastatic dissemination in vitro and in vivo by controlling FAK expression and localization. RA plus FAKi exacerbated these effects suggesting that the sensibility to RA therapies could be increased with FAKi coadministration in BC tumors.

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Section: Discussionmentioning

confidence: 99%

Combination Treatment of Retinoic Acid Plus Focal Adhesion Kinase Inhibitor Prevents Tumor Growth and Breast Cancer Cells Metastasis

Castro

Mondaca

Fernandez-Muñoz

et al. 2021

Preprint

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“…Due to the heterogeneity and complexity of BrCa, traditional inspection methods, such as immunohistochemical testing, do not identify effective biomarkers to screen and evaluate BrCa ( Network, 2012 ). Researchers examined the mechanisms of the occurrence and development of BrCa from various aspects, such as gene expression disorders ( Cruz et al, 2018 ), copy number variation ( Long et al, 2018 ; Yang et al, 2019 ) and DNA methylation ( Kresovich et al, 2019 ; Yari and Rahimi, 2019 ). Although these studies achieved promising results, they were primarily limited to the transcriptional level, and the post-transcriptional level, such as alternative splicing (AS), was neglected.…”

Section: Introductionmentioning

confidence: 99%

Correlations Between the Characteristics of Alternative Splicing Events, Prognosis, and the Immune Microenvironment in Breast Cancer

Deng

Zhao

et al. 2021

Front. Genet.

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ObjectiveAlternative splicing (AS) is the mechanism by which a few genes encode numerous proteins, and it redefines the concept of gene expression regulation. Recent studies showed that dysregulation of AS was an important cause of tumorigenesis and microenvironment formation. Therefore, we performed a systematic analysis to examine the role of AS in breast cancer (Breast Cancer, BrCa) progression.MethodsThe present study included 993 BrCa patients from The Cancer Genome Atlas (TCGA) database in the genome-wide analysis of AS events. We used differential and prognostic analyses and found differentially expressed alternative splicing (DEAS) events and independent prognostic factors related to patients’ overall survival (OS) and disease-free survival (DFS). We divided the patients into two groups based on these AS events and analyzed their clinical features, molecular subtyping and immune characteristics. We also constructed a splicing factor (SF) regulation network for key AS events and verified the existence of AS events in tissue samples using real-time quantitative PCR.ResultsA total of 678 AS events were identified as differentially expressed, of which 13 and 10 AS events were independent prognostic factors of patients’ OS and DFS, respectively. Unsupervised clustering analysis based on these prognostic factors indicated that the Cluster 1 group had a better prognosis and more immune cell infiltration. SFs were significantly related to the expression of AS events, and AA-RPS21 was significantly upregulated in tumors.ConclusionAlternative splicing expands the mechanism of breast cancer progression from a new perspective. Notably, alternative splicing may affect the patient’s prognosis by affecting the infiltration of immune cells. Our research provides important guidance for subsequent studies of AS in breast cancer.

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“…14 Yari et al indicated that patients with breast cancer were reported to have higher levels of DNA methylation compared to normal individual. 15 In addition, some researches indicated a marked relationship between the methylation level of gene and susceptibility to breast cancer. 15,16 Moreover, the promoter methylation is closely associated with the gene expression, and some DNA methylation markers have been proven to have prognostic value.…”

Section: Introductionmentioning

confidence: 99%

“…15 In addition, some researches indicated a marked relationship between the methylation level of gene and susceptibility to breast cancer. 15,16 Moreover, the promoter methylation is closely associated with the gene expression, and some DNA methylation markers have been proven to have prognostic value. 17 In this study, differentially methylated CpG sites were screened using Illumina Infinium Methylation EPIC BeadChip between breast cancer tissues and adjacent normal tissues.…”

Section: Introductionmentioning

confidence: 99%

<p>HOPX Is an Epigenetically Inactivated Tumor Suppressor and Overexpression of HOPX Induce Apoptosis and Cell Cycle Arrest in Breast Cancer</p>

You¹,

Geng²,

Ye³

et al. 2020

OTT

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Background: Evidence has been shown that abnormal DNA methylation plays a vital role in the progression of breast cancer via silencing of gene expression. The results of bisulfite sequencing showed that the methylation status of HOPX in breast cancer tissues was higher than that in normal breast cancer tissues, but little known about the biological functions of HOPX in breast cancer. Methods: A total of 13 paired breast cancer and adjacent noncancerous tissues were subjected to bisulfite sequencing. Meanwhile, the methylation levels of cg218995965 and cg24862548 in breast cancer cells were detected by methylation-specific PCR (MSP). Flow cytometry, wound healing and transwell invasion assays were used to detect the apoptosis, migration and invasion in breast cancer cells. In addition, the expressions of HOPX, p21, cyclin D1 and CDK4 in cells were detected with Western blot assay. Results: Bisulfite sequencing indicated that the CpG sites (cg218995965 and cg24862548) in the HOPX promoter region showed significantly higher methylation in breast cancer tissues. In addition, methylation-specific PCR revealed that HOPX was significantly hypermethylated in breast cancer cell lines MDA-MB-468 and MCF-7. Furthermore, overexpression of HOPX significantly inhibited the proliferation of MDA-MB-468 and MCF-7 cells via inducing the apoptosis. Moreover, upregulation of HOPX markedly inhibited the migration and invasion abilities of MDA-MB-468 cells. Meanwhile, overexpression of HOPX obviously induced cell cycle arrest in MDA-MB-468 cells via upregulation of p21, and downregulation of cyclin D1 and CDK4. Additionally, overexpression of HOPX suppressed tumor growth of breast cancer in vivo. Conclusion: Our data showed that HOPX, a tumor suppressor, is epigenetically silenced in breast cancer. Overexpression of HOPX could suppress the progression of breast cancer, and thus indicating that it might serve as a potential target for the treatment of patients with breast cancer.

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Promoter Methylation Status of the Retinoic Acid Receptor-Beta 2 Gene in Breast Cancer Patients: A Case Control Study and Systematic Review

Cited by 12 publications

References 43 publications

Combination Treatment of Retinoic Acid Plus Focal Adhesion Kinase Inhibitor Prevents Tumor Growth and Breast Cancer Cells Metastasis

Combination Treatment of Retinoic Acid Plus Focal Adhesion Kinase Inhibitor Prevents Tumor Growth and Breast Cancer Cells Metastasis

Correlations Between the Characteristics of Alternative Splicing Events, Prognosis, and the Immune Microenvironment in Breast Cancer

<p>HOPX Is an Epigenetically Inactivated Tumor Suppressor and Overexpression of HOPX Induce Apoptosis and Cell Cycle Arrest in Breast Cancer</p>

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