scholarly journals Sirt3 Exerts Its Tumor-Suppressive Role by Increasing p53 and Attenuating Response to Estrogen in MCF-7 Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 294 ◽  
Author(s):  
Marija Pinterić ◽  
Iva I. Podgorski ◽  
Marijana Popović Hadžija ◽  
Vedrana Filić ◽  
Mladen Paradžik ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Inhibitory Effect ◽  
Breast Cancers ◽  
Proliferative Effect ◽  
Er Positive ◽  
And Migration ◽  
Tumor Suppressive Function ◽  
Mcf 7

Estrogen (E2) is a major risk factor for the initiation and progression of malignancy in estrogen receptor (ER) positive breast cancers, whereas sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, has the inhibitory effect on the tumorigenic properties of ER positive MCF-7 breast cancer cells. Since it is unclear if this effect is mediated through the estrogen receptor alpha (ERα) signaling pathway, in this study, we aimed to determine if the tumor-suppressive function of Sirt3 in MCF-7 cells interferes with their response to E2. Although we found that Sirt3 improves the antioxidative response and mitochondrial fitness of the MCF-7 cells, it also increases DNA damage along with p53, AIF, and ERα expression. Moreover, Sirt3 desensitizes cells to the proliferative effect of E2, affects p53 by disruption of the ERα–p53 interaction, and decreases proliferation, colony formation, and migration of the cells. Our observations indicate that these tumor-suppressive effects of Sirt3 could be reversed by E2 treatment only to a limited extent which is not sufficient to recover the tumorigenic properties of the MCF-7 cells. This study provides new and interesting insights with respect to the functional role of Sirt3 in the E2-dependent breast cancers.

Effect of farrerol on the proliferation of estrogen receptor-positive breast cancer by downregulating oncogenic genes with estrogen receptor response elements.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12541-e12541
Author(s):  
Xiao-Qing Lu ◽  
Rui Yang ◽  
Jia-Qian Zhang ◽  
Shengxiao Zhang ◽  
Huan-Hu Zhang
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Molecular Docking ◽  
Mammary Epithelial Cells ◽  
Inhibitory Effect ◽  
Mammary Epithelial ◽  
Cell Group ◽  
Response Elements ◽  
Er Positive ◽  
Mcf 7

e12541 Background: Breast cancer (BC) is the most common malignant tumor among women worldwide, the most common of which is estrogen receptor (ER) -positive BC. Farrerol, a noval estrogen-like chemicals, is closely associated with ER positive BC. In this study, we will explore the anticancer effect of farrerol on ER-positive BC and the detailed mechanism. Methods: Cloning formation assay and MTT assay were used to evaluate the effect of farrerol on proliferation ofcells. The affinity of farrerol, estrogen and tamoxifen with ER was tested by molecular docking technique. Point mutation was performed on the possible binding sites of ER according to the results of virtual docking, and Surface Plasmon Resonance (SPR). ER response elements in BC cells with farrerol were evaluated by qPCR. Results: With the increased farrerol concentration, the number of cell clones formed gradually decreased and the volume of clones became smaller in the ER positive McF-7 cell group, while a completely opposite clones was observed in non- ER positive MDA-MB-231 cells. The proliferation inhibition rate of McF-7 cells in the 160 mol/L and 320 mol/L groups was 45.86% and 65.3% respectively, significantly higher than that of MDA-MB-231 and normal mammary epithelial cells (P < 0.05). Both molecular docking technique and SPR experiment showed that farrerol could bind to ER at different sites than estrogen binding. Fiarrerol effectively down-regulated the transcription of the oncogenes MYC and TFF1, and suppressed ER-positive BC. Conclusions: Farrerol has the opposite effect with estrogen, which inhibited the proliferation of ER-positive BC cells, and downregulated the expression of oncogenic genes with ER response elements in BC cells. Therefore, farrerol, as a natural ingredient, could be further developed and applied with its obvious inhibitory effect on ER-positive BC in the future.

scholarly journals The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1122 ◽  
Author(s):  
Jones ◽  
Wilson ◽  
Thomas ◽  
Gaughan ◽  
Wade
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Therapeutic Option ◽  
Global Gene Expression ◽  
Gene Signature ◽  
Inhibitory Effect ◽  
Breast Cancers ◽  
Er Positive ◽  
Environment Control ◽  
Transcriptional Complex

Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators has therefore been proposed as a novel therapeutic approach. By assessing DNA-binding dynamics in ER-positive breast cancer cells, we have identified that the histone H3 lysine 9 demethylase enzymes, KDM3A and KDM4B, co-operate to regulate ER activity via an auto-regulatory loop that facilitates the recruitment of each co-activating enzyme to chromatin. We also provide evidence that suggests that KDM3A primes chromatin for deposition of the ER pioneer factor FOXA1 and recruitment of the ER-transcriptional complex, all prior to ER recruitment, therefore establishing an important mechanism of chromatin regulation involving histone demethylases and pioneer factors, which controls ER functionality. Importantly, we show via global gene-expression analysis that a KDM3A/KDM4B/FOXA1 co-regulated gene signature is enriched for pro-proliferative and ER-target gene sets, suggesting that abrogation of this network could be an efficacious therapeutic strategy. Finally, we show that depletion of both KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than knockdown of each individual enzyme, suggesting that targeting both enzymes represents a potentially efficacious therapeutic option for ER-driven breast cancer.

scholarly journals DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Z. Awada ◽  
R. Nasr ◽  
R. Akika ◽  
V. Cahais ◽  
C. Cuenin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Dna Methylome ◽  
Cancer Data ◽  
Normal Tissues ◽  
Chemical Structures ◽  
Er Positive ◽  
Clinical Breast ◽  
And Migration ◽  
Mcf 7

Abstract Background Bisphenol A (BPA), an estrogen-like endocrine disruptor used in plastics, has been associated with development and promotion of breast cancer, so plastic manufacturers shifted towards less-studied analogs, BPF and BPS. Studying the associated DNA methylome-wide mechanisms of these derivatives is timely, particularly in comparison with BPA. Methods We assessed proliferation, cell cycle, and migration of breast cancer cells (estrogen receptor (ER)-positive: MCF-7 and ER-negative: MDA-MB-231) treated with BPF and BPS ± estrogen receptor inhibitor (ERI) in comparison to BPA ± ERI. RNA expression and activity of DNA (de)methylation enzymes and LINE-1 methylation were quantified. DNA methylome-wide analysis was evaluated in bisphenol-exposed cells and compared to clinical breast cancer data. Results The three bisphenols caused ER-dependent increased proliferation and migration of MCF-7 but not MDA-MB-231 cells, with BPS being 10 times less potent than BPA and BPF. Although they have similar chemical structures, the three bisphenols induced differential DNA methylation alterations at several genomic clusters of or single CpG sites, with the majority of these being ER-dependent. At equipotent doses, BPA had the strongest effect on the methylome, followed by BPS then BPF. No pathways were enriched for BPF while BPA- and BPS-induced methylome alterations were enriched in focal adhesion, cGMP-PKG, and cancer pathways, which were also dysregulated in methylome-wide alterations comparing ER-positive breast cancer samples to adjacent normal tissues. Conclusions The three bisphenols have important epigenetic effects in breast cell lines, with those of BPA and BPS overlapping with cancer-related pathways in clinical breast cancer models. Hence, further investigation of their safety is warranted.

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