Epigenetic silencing of
            <scp>SALL</scp>
            2 confers tamoxifen resistance in breast cancer

Ye, Liping; Lin, Chuyong; Wang, Xi; Li, Qiji; Li, Yue; Wang, Meng; Zhao, Zhibin; Wu, Xiao; Shi, Dongni; Xiao, Yunyun; Lang, Ren; Jian, Yunting; Yang, Meisongzhu; Ou, Ruizhang; Deng, Guangzheng; Ouyang, Ying; Chen, Xiangfu; Li, Jun; Song, Libing

doi:10.15252/emmm.201910638

Cited by 56 publications

(38 citation statements)

References 50 publications

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“…A number of transcription factors regulating NFκB1 and PTEN were identified as direct or indirect targets of miRNA. SALL2 and SALL4 are positive regulators of PTEN and can regulate tumor metastasis [ 53 , 54 ]. In our analysis, SALL4 expression was significantly downregulated in miRNA-high cell lines compared to MCF7.…”

Section: Discussionmentioning

confidence: 99%

Chemically Induced Hypoxia Enhances miRNA Functions in Breast Cancer

Gervin

Shin

Opperman

et al. 2020

Cancers

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In aggressively growing tumors, hypoxia induces HIF-1α expression promoting angiogenesis. Previously, we have shown that overexpression of oncogenic microRNAs (miRNAs, miRs) miR526b/miR655 in poorly metastatic breast cancer cell lines promotes aggressive cancer phenotypes in vitro and in vivo. Additionally, miR526b/miR655 expression is significantly higher in human breast tumors, and high miR526b/miR655 expression is associated with poor prognosis. However, the roles of miR526b/miR655 in hypoxia are unknown. To test the relationship between miR526b/miR655 and hypoxia, we used various in vitro, in silico, and in situ assays. In normoxia, miRNA-high aggressive breast cancer cell lines show higher HIF-1α expression than miRNA-low poorly metastatic breast cancer cell lines. To test direct involvement of miR526b/miR655 in hypoxia, we analyzed miRNA-high cell lines (MCF7-miR526b, MCF7-miR655, MCF7-COX2, and SKBR3-miR526b) compared to controls (MCF7 and SKBR3). CoCl2-induced hypoxia in breast cancer further promotes HIF-1α mRNA and protein expression while reducing VHL expression (a negative HIF-1α regulator), especially in miRNA-high cell lines. Hypoxia enhances oxidative stress, epithelial to mesenchymal transition, cell migration, and vascular mimicry more prominently in MCF7-miR526b/MCF7-miR655 cell lines compared to MCF7 cells. Hypoxia promotes inflammatory and angiogenesis marker (COX-2, EP4, NFκB1, VEGFA) expression in all miRNA-high cells. Hypoxia upregulates miR526b/miR655 expression in MCF7 cells, thus observed enhancement of hypoxia-induced functions in MCF7 could be attributed to miR526b/miR655 upregulation. In silico bioinformatics analysis shows miR526b/miR655 regulate PTEN (a negative regulator of HIF-1α) and NFκB1 (positive regulator of COX-2 and EP4) expression by downregulation of transcription factors NR2C2, SALL4, and ZNF207. Hypoxia-enhanced functions in miRNA-high cells are inhibited by COX-2 inhibitor (Celecoxib), EP4 antagonist (ONO-AE3-208), and irreversible PI3K/Akt inhibitor (Wortmannin). This establishes that hypoxia enhances miRNA functions following the COX-2/EP4/PI3K/Akt pathways and this pathway can serve as a therapeutic target to abrogate hypoxia and miRNA induced functions in breast cancer. In situ, HIF-1α expression is significantly higher in human breast tumors (n = 96) compared to non-cancerous control tissues (n = 20) and is positively correlated with miR526b/miR655 expression. In stratified tumor samples, HIF-1α expression was significantly higher in ER-positive, PR-positive, and HER2-negative breast tumors. Data extracted from the TCGA database also show a strong correlation between HIF-1α and miRNA-cluster expression in breast tumors. This study, for the first time, establishes the dynamic roles of miR526b/miR655 in hypoxia.

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Section: Discussionmentioning

confidence: 99%

Chemically Induced Hypoxia Enhances miRNA Functions in Breast Cancer

Gervin

Shin

Opperman

et al. 2020

Cancers

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“…The downregulation of SALL2 is reported to repress ESR1 transcription, thus creating tamoxifen-resistant tumours. 30 Further, breast-tissue-specific hypermethylation of CpG islands strongly linked with estrogen-receptor positivity and with consequences for gene transcription has been reported. 58 Amidst the rich genomic-diversity of African populations, 59 which remains poorly explored, evaluating the possibility of a crosstalk between methylome evolution and a heightened genome instability 56,57 in Nigerian patients may prove pivotal in the delivery of effective tamoxifen therapy for the population.…”

Section: Breast Tumour Genome Methylome and Tamoxifen Therapymentioning

confidence: 98%

<p>Breast Cancer and Tamoxifen: A Nigerian Perspective to Effective Personalised Therapy</p>

Adehin

Kennedy

Soyinka

et al. 2020

BCTT

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Estrogen-receptor positivity in tumour, often requiring long-term tamoxifen therapy, is thought to characterise between 43% and 65% of breast cancer cases in Nigeria. The patient population is further marked by late-stage diagnosis which significantly heightens the tendency for tumour relapse in the course of tamoxifen therapy. Despite tamoxifen being considered a reliable chemopreventive in high-risk individuals and an effective adjuvant therapy for hormone-sensitive tumours, mortality has remained high among breast cancer patients in the West African region where Nigeria belongs. The Nigerian breast cancer population, like other similar patient-populations in the West African region, provides a mix of intrinsic genome-diversity and perhaps unique tumour biology and evolution. These peculiarities suggest the need for a rational approach to tumour management and a personalised delivery of therapy in Nigeria's dominant estrogen-receptorpositive patient population. Herein, critical indices of tamoxifen-therapy success are discussed in the context of the Nigerian breast cancer population with emphasis on salient aspects of tamoxifen-biotransformation, host-and tumour-genomics, and epigenetics.

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“…levels of estrogen receptor-alpha (ERα) and PTEN, which causes the continued activation of AKT/mTOR. In addition, hypomethylation of SALL2 increases its expression, leading to the upregulation of ER and PTEN and the further inhibition of the AKT/mTOR signaling pathway, which consequently leads to TAM sensitivity (210). Among breast cancers, 15-20% are human epidermal growth factor receptor 2 positive (HER2+) and may develop resistance to trastuzumab.…”

Section: Regulation Of the Pi3k/pten/akt/mtor Signaling Pathway By Dnmentioning

confidence: 99%

“…SALL2 decreased expression promotes decreased expression levels of estrogen receptor-alpha (ERα) and PTEN, which causes the continued activation of AKT/mTOR. In addition, hypomethylation of SALL2 increases its expression, leading to the upregulation of ER and PTEN and the further inhibition of the AKT/mTOR signaling pathway, which consequently leads to TAM sensitivity ( 210 ).…”

Section: Regulation Of the Pi3k/pten/akt/mtor Signaling Pathway By Dnmentioning

confidence: 99%

Role of DNA Methylation in the Resistance to Therapy in Solid Tumors

Romero-García¹,

Prado-Garcı́a²,

Carlos‐Reyes³

2020

Front. Oncol.

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Despite the recent advances in chemotherapeutic treatments against cancer, some types of highly aggressive and invasive cancer develop drug resistance against conventional therapies, which continues to be a major problem in the fight against cancer. In recent years, studies of alterations of DNA methylome have given us a better understanding of the role of DNA methylation in the development of tumors. DNA methylation (DNAm) is an epigenetic change that promotes the covalent transfer of methyl groups to DNA. This process suppresses gene expression through the modulation of the transcription machinery access to the chromatin or through the recruitment of methyl binding proteins. DNAm is regulated mainly by DNA methyltransferases. Aberrant DNAm contributes to tumor progression, metastasis, and resistance to current anti-tumoral therapies. Aberrant DNAm may occur through hypermethylation in the promoter regions of tumor suppressor genes, which leads to their silencing, while hypomethylation in the promoter regions of oncogenes can activate them. In this review, we discuss the impact of dysregulated methylation in certain genes, which impact signaling pathways associated with apoptosis avoidance, metastasis, and resistance to therapy. The analysis of methylome has revealed patterns of global methylation, which regulate important signaling pathways involved in therapy resistance in different cancer types, such as breast, colon, and lung cancer, among other solid tumors. This analysis has provided gene-expression signatures of methylated region-specific DNA that can be used to predict the treatment outcome in response to anti-cancer therapy. Additionally, changes in cancer methylome have been associated with the acquisition of drug resistance. We also review treatments with demethylating agents that, in combination with standard therapies, seem to be encouraging, as tumors that are in early stages can be successfully treated. On the other hand, tumors that are in advanced stages can be treated with these combination schemes, which could sensitize tumor cells that are resistant to the therapy. We propose that rational strategies, which combine specific demethylating agents with conventional treatment, may improve overall survival in cancer patients.

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Epigenetic silencing of SALL 2 confers tamoxifen resistance in breast cancer

Cited by 56 publications

References 50 publications

Chemically Induced Hypoxia Enhances miRNA Functions in Breast Cancer

Chemically Induced Hypoxia Enhances miRNA Functions in Breast Cancer

<p>Breast Cancer and Tamoxifen: A Nigerian Perspective to Effective Personalised Therapy</p>

Role of DNA Methylation in the Resistance to Therapy in Solid Tumors

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