scholarly journals Exposure of mammary cells to lipid activates gene expression changes associated with ER-negative breast cancer via chromatin remodeling.

2020 ◽  
Author(s):  
Shivangi Yadav ◽  
Ranya Virk ◽  
Carolina Chung ◽  
David Van Derway ◽  
Duojian Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Posttranslational Modifications ◽  
Chromatin Accessibility ◽  
Pathway Activation ◽  
Chromatin Packing ◽  
One Carbon Metabolism ◽  
Vitro Model ◽  
Lipid Metabolism Genes

Improved understanding of local breast biology that favors the development of estrogen receptor-negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A cells and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC.

scholarly journals Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Michelle C Ward ◽  
Nicholas E Banovich ◽  
Abhishek Sarkar ◽  
Matthew Stephens ◽  
Yoav Gilad
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Induced Pluripotent Stem Cell ◽  
Chromatin Accessibility ◽  
Regulatory Changes ◽  
Life Threatening ◽  
Vitro Model ◽  
Culturing Conditions ◽  
Induced Pluripotent

One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia, and short- or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.

Investigating tamoxifen resistance in the luminal B estrogen receptor positive breast cancer subtype: Tailoring treatment in hormone responsive breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10603-10603 ◽  
Author(s):  
S. Loi ◽  
C. Sotiriou ◽  
B. Haibe-Kains ◽  
F. Lallemand ◽  
N. Conus ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Her2 Overexpression ◽  
Mcf7 Cells ◽  
Luminal A ◽  
Gene Set ◽  
Luminal B ◽  
Vitro Model ◽  
Her2 Signaling

10603 Background: We recently reported that the two estrogen receptor (ER) positive breast cancer (BC) molecular subtypes can be defined by their expression of proliferation genes using a gene expression index (GGI): the luminal A and B subtypes have low and high levels respectively (J Clin Onc, in press). When treated with adjuvant tamoxifen, luminal A tumors have a good prognosis, however the clinical outcome of the luminal B subtype was poor. This study aimed to explain the biological basis for these observations using global gene expression profiling and an in vitro model of ER+ BC. Methods: 246 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy were analyzed with affymetrix gene expression arrays and evaluated using gene set enrichment analysis (GSEA). ER+ MCF-7 BC cells (control) treated with tamoxifen (TAM) and heregulin (HRG) were used to investigate molecular pathways identified using GSEA. Results: We found that a gene set suggesting ERBB2 pathway activation was significantly enriched in the luminal B subtype (p=0.02). Only 10% of samples overexpressed HER2 by immunohistochemistry, suggesting that activation of HER2 signaling pathways is independent of HER2 overexpression and may contribute to TAM resistance in this subtype. To validate this hypothesis, MCF-7 cell-lines were treated with HRG (HRG-MCF7) to create a model of ERBB2 pathway activation. HRG-MCF7 cells displayed phosphorylation of HER2/3 without HER2 overexpression. Treatment with HRG overcame TAM induced cell cycle arrest with higher S-phase fraction (p<0.01) and increased anchorage- independent colony formation (p<0.01). Gene expression profiling confirmed significant enrichment of the ERBB2 gene set (p<0.01) and higher GGI levels (p=0.02) in HRG-MCF7 cells compared with control. Conclusions: HRG-MCF7 cells may be useful as an in vitro model of the TAM resistant luminal B subtype. In this group, targeting activated HER2 signaling may be a helpful treatment strategy despite the lack of HER2 overexpression. Our data suggests that agents like lapatinib may be effective only in the luminal B and not the luminal A tumors, demonstrating the importance of stratifying by subtype in future clinical trials of ER+ disease. No significant financial relationships to disclose.

Coumarin-Fatty Acid Conjugates as Potential ERα/AKT-1 Antagonists for ER Positive Breast Cancer

2020 ◽  
Vol 20 (4) ◽  
pp. 437-449
Author(s):  
Jubie Selvaraj ◽  
Jameera B.A. John ◽  
Nanjan M. Joghee ◽  
Justin Antony ◽  
Ashish Wadhwani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Fatty Acid ◽  
Binding Assay ◽  
Uterine Cancer ◽  
Design Development ◽  
Structure Based Drug Design ◽  
Ic50 Values ◽  
Cancer Activity

Background: : Current drugs used for the treatment of hormone-dependent breast cancer function as anti-estrogens in the breast, in addition to Estrogen Receptor (ER) agonists in the uterus, thus elevate a woman’s risk of developing uterine cancer. This is due to the lack of selective binding and partial agonistic effect of these drugs towards estrogen receptors. In recent years, therefore, researchers have turned their attention towards antiestrogens devoid of these agonist properties and thus have a mechanism of action different from the existing drugs. Objective:: In this context, we report here the design, development and in vitro evaluation of some novel pharmacophores containing coumarin and fatty acid scaffolds for their anti-breast cancer activity. Methods: : A library of coumarin-fatty acid conjugates was designed using structure-based drug design approach. The conjugates which have shown good in silico results were then synthesized, characterized and evaluated for their anti-breast cancer activity by MTT assay, Apoptotic assay, Cell proliferation assay, Estrogen binding assay and Gene expression study. Results: Out of the fifteen compounds screened, two compounds, SAC-2 and LNAC-2, showed good activity with IC50 values 22µg/ml, 25μg/ml, respectively. These compounds suppressed the proliferation of ER overexpressed MCF-7 cells, increased ERα degradation and hence inactivate the ERα pathway. ER binding assay and gene expression RT-PCR study reveal that SAC-2 downregulated the expression of ERα receptor and AKT-1 gene. Conclusion:: Compound SAC-2 is a good antagonist to ER and hence has a potential for treating breast cancer and other cancers where AKT plays an important role.

scholarly journals Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2806
Author(s):  
Lucie Storz ◽  
Philipp Walther ◽  
Olga Chemnitzer ◽  
Orestis Lyros ◽  
Stefan Niebisch ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Squamous Epithelium ◽  
Acid Reflux ◽  
Cellular Damage ◽  
Pathway Activation ◽  
Cellular Context ◽  
Vitro Model ◽  
Nfκb Pathway ◽  
Eac Cells

Chronic acid reflux causes cellular damage and inflammation in the lower esophagus. Due to these irritating insults, the squamous epithelium is replaced by metaplastic epithelium, which is a risk factor for the development of esophageal adenocarcinoma (EAC). In this study, we investigated the acid susceptibility in a Barrett’s cell culture in vitro model, using six cell lines, derived from squamous epithelium (EPC1 and EPC2), metaplasia (CP-A), dysplasia (CP-B), and EAC (OE33 and OE19) cells. Cells exposed to acidic pH showed a decreased viability dependent on time, pH, and progression status in the Barrett’s sequence, with the highest acid susceptibility in the squamous epithelium (EPC1 and EPC2), and the lowest in EAC cells. Acid pulsing was accompanied with an activation of the Nrf2/Keap1- and the NFκB-pathway, resulting in an increased expression of HO1—independent of the cellular context. OE33 showed a decreased responsiveness towards 5-FU, when the cells were grown in acidic conditions (pH 6 and pH 5.5). Our findings suggest a strong damage of squamous epithelium by gastroesophageal reflux, while Barrett’s dysplasia and EAC cells apparently exert acid-protective features, which lead to a cellular resistance against acid reflux.

scholarly journals CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 525 ◽  
Author(s):  
Alexander Ring ◽  
Cu Nguyen ◽  
Goar Smbatyan ◽  
Debu Tripathy ◽  
Min Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Creb Binding Protein ◽  
Novel Therapeutic

Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding protein (CREBBP or CBP) has been implicated in CSC biology and may provide a novel therapeutic target in TNBC. Methods: RNA Seq pre- and post treatment with the CBP-binding small molecule ICG-001 was used to characterize CBP-driven gene expression in TNBC cells. In vitro and in vivo TNBC models were used to determine the therapeutic effect of CBP inhibition via ICG-001. Tissue microarrays (TMAs) were used to investigate the potential of CBP and associated proteins as biomarkers in TNBC. Results: The CBP/ß-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of CBP/β-catenin/FOXM1 with ICG-001 eliminated CSCs and sensitized TNBC tumors to chemotherapy. Immunohistochemistry of TMAs demonstrated a significant correlation between FOXM1 expression and TNBC subtype. Conclusion: CBP/β-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/β-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials.

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