Abstract 467: Hypertension and Cancer: Are They Related?

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hanh T Tran ◽  
John J Gildea ◽  
Robin A Felder
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cell Motility ◽  
Cancer Progression ◽  
Kinase Inhibitor ◽  
Cancer Cell Line ◽  
Soft Agar ◽  
Mcf7 Cells ◽  
Link Type

There are literature references supporting a link between hypertension and cancer. However, a mechanism for this association has not been defined. Key players in blood pressure regulation include the dopamine-1 receptor (D 1 R), G protein-coupled kinase type 4 (GRK4) and c-Myc, all found in renal proximal tubule cells (RPTC). c-Myc also regulates GRK4 in the breast cancer cell line MCF7. We hypothesized that the D 1 R would act as a tumor suppressor and both GRK4 and c-Myc as oncogenes in MCF7 cells. GRK4 is positively regulated transcriptionally by c-Myc, and GRK4 is negatively regulated by Caveolin-1 (CAV1) in RPTCs, so we tested if the same relationship occurs in this breast cancer model. SKF38393 (D 1 R agonist, 10μM, 18hr) reduced wild type MCF7 (WT-MCF7) cell motility (an index of aggressive growth) by 16.0% ± 3.2 SEM (n=9; p<0.005; 115393/137330 RFU), while the D 1 R antagonist LE300 (10μM, 18hr) increased cell motility 23.0% ± 7.0 SEM (n=9; p<0.05; 168955/137330 RFU). CAV1, a tumor suppressor and GRK4 kinase inhibitor, is missing in MCF7, so we transfected CAV1 into MCF7 cells (CAV-MCF7) and inhibited cell motility even further following SKF38393 stimulation (29.8% ± 2.8 SEM; n=11; p<0.005 vs.WT-MCF7; 105801/150766 RFU). CAV1 binding to GRK4 was verified by co-immunoprecipitation. CAV-MCF7 also showed higher levels of basal cell surface D 1 R (103.3% ± 35.9 SEM; n=10; p<0.01 vs WT-MCF7; 808/397 RFU) and D 1 R membrane recruitment post-fenoldopam stimulation (FEN, D 1 R agonist, 10μM, 30min) (increase of 65.5% ± 6.18 SEM; n=4; p<0.05 vs. WT-MCF7; 1.65/1.00 RFU). We verified that CAV-MCF7 showed decreased soft agar colony growth and decreased rates of cell proliferation. Because c-Myc increases GRK4 expression, cell proliferation after c-Myc knock down (KD-MCF7) was tested. KD-MCF7 showed decreased cell proliferation at 48 hr by 37.7% ± 7.6 SEM (n=3; p<0.05 vs WT-MCF7; 2752/4416 cells), while both knockdown of c-Myc and re-expression of GRK4 restored proliferation by 23.1% ± 13.4 SEM (n=10; p<0.05 vs KDMCF; 1346/1093 cells) at 96 hr. We therefore conclude that c-Myc activation of GRK4 inactivates the dopaminergic pathway in both the kidney and breast cancer progression which may be a common link between hypertension and breast cancer.

scholarly journals DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 282 ◽  
Author(s):  
Ravikiran Mahadevappa ◽  
Henrique Neves ◽  
Shun Yuen ◽  
Muhammad Jameel ◽  
Yuchen Bai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Dna Replication ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Cancer Cell Line ◽  
Breast Cancer Progression

Breast cancer is one of the most common malignancies in women worldwide. In breast cancer, the cell proliferation rate is known to influence the cancer malignancy. Recent studies have shown that DNA replication initiation/licensing factors are involved in cancer cell proliferation as well as cancer cell migration and invasion. Licensing factors have also been reported as important prognostic markers in lung, prostrate, and bladder cancers. Here, we studied the role of MCM10, a novel licensing factor, in breast cancer progression. From the public database, NCBI, we investigated six independent breast cancer patient cohorts, totaling 1283 patients. We observed a significant association between high MCM10 mRNA expression with tumor grading and patients’ survival time. Most importantly, using breast cancer cohorts with available treatment information, we also demonstrated that a high level of MCM10 is associated with a better response to conventional treatment. Similarly, in in vitro studies, the expression level of MCM10 in breast cancer cell lines is significantly higher compared to paired normal breast epithelium cells. Knockdown of MCM10 expression in the cancer cell line showed significantly decreased tumorigenic properties such as cell proliferation, migration and anchorage independence. The MCF7 breast cancer cell line, after MCM10 expression knockdown, showed significantly decreased tumorigenic properties such as cell proliferation, migration, and anchorage independent growth. Mechanistically, MCM10 expression is observed to be regulated by an Estrogen Receptor (ER) signaling pathway, where its expression is suppressed by the inhibition of the ER or serum withdrawal. Our results suggest that MCM10 plays an important role in breast cancer progression and is a potential prognostic/predictive biomarker and therapeutic target for breast cancer patients.

Continuous Hypoxia and Glucose Metabolism, The Effects on Genes Expression in Mcf7 Breast Cancer Cell Line

2020 ◽  
Vol 20 ◽  
Author(s):  
Abdel Qader Al Bawab ◽  
Malek Zihlif ◽  
Yazan Jarrar ◽  
Ahmad Saleh
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Cell Line ◽  
Breast Cancer Cell Line ◽  
Warburg Effect ◽  
Cancer Cell Line ◽  
Mcf7 Cells ◽  
Genetic Changes ◽  
Genes Expression

Background: Hypoxia (deprived oxygen in tissues) may induce molecular and genetic changes in cancer cells. Objective: Investigating the genetic changes of glucose metabolism in breast cancer cell line (MCF7) after exposure to continuous hypoxia (10 and 20 cycles exposure of 72 hours continuously on a weekly basis). Method: Gene expression of MCF7 cells was evaluated using real-time polymerase chain reaction- array method. Furthermore, cell migration and wound healing assays were also applied. Results: It was found that 10 episodes of continuous hypoxia activated Warburg effect in MCF7 cells via the significant up-regulation of genes involved in glycolysis (ANOVA, p value < 0.05). The molecular changes were associated with the ability of MCF7 cells to divide and migrate. Interestingly, after 20 episodes of continuous hypoxia, the expression glycolysis mediated genes has dropped significantly (from 30 to 9 folds). This could be attributed to the adaptive ability of cancer cells. Conclusion: It is concluded that 10 hypoxic episodes increased the survival rate and the aggressiveness of MCF7 cells and induced Warburg effect by up-regulation of the glycolysis mediating genes expression.

scholarly journals Expression and Function of C1orf132 Long-Noncoding RNA in Breast Cancer Cell Lines and Tissues

2021 ◽  
Vol 22 (13) ◽  
pp. 6768
Author(s):  
Afsaneh Malekzadeh Shafaroudi ◽  
Ali Sharifi-Zarchi ◽  
Saeid Rahmani ◽  
Nahid Nafissi ◽  
Seyed Javad Mowla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Breast Cancer Cell Lines ◽  
Mcf7 Cells ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
Migration Assay ◽  
And Function ◽  
Distal Promoter

miR-29b2 and miR-29c play a suppressive role in breast cancer progression. C1orf132 (also named MIR29B2CHG) is the host gene for generating both microRNAs. However, the region also expresses longer transcripts with unknown functions. We employed bioinformatics and experimental approaches to decipher C1orf132 expression and function in breast cancer tissues. We also used the CRISPR/Cas9 technique to excise a predicted C1orf132 distal promoter and followed the behavior of the edited cells by real-time PCR, flow cytometry, migration assay, and RNA-seq techniques. We observed that C1orf132 long transcript is significantly downregulated in triple-negative breast cancer. We also identified a promoter for the longer transcripts of C1orf132 whose functionality was demonstrated by transfecting MCF7 cells with a C1orf132 promoter-GFP construct. Knocking-out the promoter by means of CRISPR/Cas9 revealed no alterations in the expression of the neighboring genes CD46 and CD34, while the expression of miR-29c was reduced by half. Furthermore, the promoter knockout elevated the migration ability of the edited cells. RNA sequencing revealed many up- and downregulated genes involved in various cellular pathways, including epithelial to mesenchymal transition and mammary gland development pathways. Altogether, we are reporting here the existence of an additional/distal promoter with an enhancer effect on miR-29 generation and an inhibitory effect on cell migration.

scholarly journals Role of the V1G1 subunit of V-ATPase in breast cancer cell migration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria De Luca ◽  
Roberta Romano ◽  
Cecilia Bucci
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Downstream Signaling ◽  
Late Endosomes ◽  
Intracellular Compartments

AbstractV-ATPase is a large multi-subunit complex that regulates acidity of intracellular compartments and of extracellular environment. V-ATPase consists of several subunits that drive specific regulatory mechanisms. The V1G1 subunit, a component of the peripheral stalk of the pump, controls localization and activation of the pump on late endosomes and lysosomes by interacting with RILP and RAB7. Deregulation of some subunits of the pump has been related to tumor invasion and metastasis formation in breast cancer. We observed a decrease of V1G1 and RAB7 in highly invasive breast cancer cells, suggesting a key role of these proteins in controlling cancer progression. Moreover, in MDA-MB-231 cells, modulation of V1G1 affected cell migration and matrix metalloproteinase activation in vitro, processes important for tumor formation and dissemination. In these cells, characterized by high expression of EGFR, we demonstrated that V1G1 modulates EGFR stability and the EGFR downstream signaling pathways that control several factors required for cell motility, among which RAC1 and cofilin. In addition, we showed a key role of V1G1 in the biogenesis of endosomes and lysosomes. Altogether, our data describe a new molecular mechanism, controlled by V1G1, required for cell motility and that promotes breast cancer tumorigenesis.

scholarly journals Reversal of hypermethylation and reactivation of glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line

Tumor Biology ◽  
2017 ◽  
Vol 39 (2) ◽  
pp. 101042831769225 ◽  
Author(s):  
Umesh Kumar ◽  
Ujjawal Sharma ◽  
Garima Rathi
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Line ◽  
Tumor Suppressor Genes ◽  
Cancer Cell Line ◽  
Methylation Pattern ◽  
Glutathione S Transferase ◽  
Suppressor Genes ◽  
Mcf 7

One of the mechanisms for epigenetic silencing of tumor suppressor genes is hypermethylation of cytosine residue at CpG islands at their promoter region that contributes to malignant progression of tumor. Therefore, activation of tumor suppressor genes that have been silenced by promoter methylation is considered to be very attractive molecular target for cancer therapy. Epigenetic silencing of glutathione S-transferase pi 1, a tumor suppressor gene, is involved in various types of cancers including breast cancer. Epigenetic silencing of tumor suppressor genes can be reversed by several molecules including natural compounds such as polyphenols that can act as a hypomethylating agent. Curcumin has been found to specifically target various tumor suppressor genes and alter their expression. To check the effect of curcumin on the methylation pattern of glutathione S-transferase pi 1 gene in MCF-7 breast cancer cell line in dose-dependent manner. To check the reversal of methylation pattern of hypermethylated glutathione S-transferase pi 1, MCF-7 breast cancer cell line was treated with different concentrations of curcumin for different time periods. DNA and proteins of treated and untreated cell lines were isolated, and methylation status of the promoter region of glutathione S-transferase pi 1 was analyzed using methylation-specific polymerase chain reaction assay, and expression of this gene was analyzed by immunoblotting using specific antibodies against glutathione S-transferase pi 1. A very low and a nontoxic concentration (10 µM) of curcumin treatment was able to reverse the hypermethylation and led to reactivation of glutathione S-transferase pi 1 protein expression in MCF-7 cells after 72 h of treatment, although the IC50 value of curcumin was found to be at 20 µM. However, curcumin less than 3 µM of curcumin could not alter the promoter methylation pattern of glutathione S-transferase pi 1. Treatment of breast cancer MCF-7 cells with curcumin causes complete reversal of glutathione S-transferase pi 1 promoter hypermethylation and leads to re-expression of glutathione S-transferase pi 1, suggesting it to be an excellent nontoxic hypomethylating agent.

scholarly journals ATG9A Is Overexpressed in Triple Negative Breast Cancer and Its In Vitro Extinction Leads to the Inhibition of Pro-Cancer Phenotypes

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 248 ◽  
Author(s):  
Aurore Claude-Taupin ◽  
Leïla Fonderflick ◽  
Thierry Gauthier ◽  
Laura Mansi ◽  
Jean-René Pallandre ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Cell Line ◽  
Cancer Tissue ◽  
The Future ◽  
Cancer Phenotypes

Early detection and targeted treatments have led to a significant decrease in mortality linked to breast cancer (BC), however, important issues need to be addressed in the future. One of them will be to find new triple negative breast cancer (TNBC) therapeutic strategies, since none are currently efficiently targeting this subtype of BC. Since numerous studies have reported the possibility of targeting the autophagy pathway to treat or limit cancer progression, we analyzed the expression of six autophagy genes (ATG9A, ATG9B, BECLIN1, LC3B, NIX and P62/SQSTM1) in breast cancer tissue, and compared their expression with healthy adjacent tissue. In our study, we observed an increase in ATG9A mRNA expression in TNBC samples from our breast cancer cohort. We also showed that this increase of the transcript was confirmed at the protein level on paraffin-embedded tissues. To corroborate these in vivo data, we designed shRNA- and CRISPR/Cas9-driven inhibition of ATG9A expression in the triple negative breast cancer cell line MDA-MB-436, in order to determine its role in the regulation of cancer phenotypes. We found that ATG9A inhibition led to an inhibition of in vitro cancer features, suggesting that ATG9A can be considered as a new marker of TNBC and might be considered in the future as a target to develop new specific TNBC therapies.

scholarly journals Potential Metabolite Nymphayol Isolated from Water Lily (Nymphaea stellata) Flower Inhibits MCF-7 Human Breast Cancer Cell Growth via Upregulation of Cdkn2a, pRb2, p53 and Downregulation of PCNA mRNA Expressions

Metabolites ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 280
Author(s):  
Laila Naif Al-Harbi ◽  
Pandurangan Subash-Babu ◽  
Manal Abdulaziz Binobead ◽  
Maha Hussain Alhussain ◽  
Sahar Abdulaziz AlSedairy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cell Viability ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Kinase Inhibitor ◽  
B Cell Lymphoma ◽  
Nuclear Antigen ◽  
Mrna Levels ◽  
Mcf 7

Controlled production of cyclin dependent kinases (CDK) and stabilization of tumor suppressor genes are the most important factors involved in preventing carcinogenesis. The present study aimed to explore the cyclin dependent apoptotic effect of nymphayol on breast cancer MCF-7 cells. In our previous study, we isolated the crystal from a chloroform extract of Nymphaea stellata flower petals and it was confirmed as nymphayol (17-(hexan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol) using x-ray diffraction (XRD), Fourier transform infrared (FTIR), and mass spectroscopy (MS) methods. The cytotoxic effect of nymphayol on MCF-7 cells were analyzed using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The cellular and nuclear damage was determined using propidium iodide (PI) and acridine orange/ethidium bromide (AO/ErBr) staining. Tumor suppressor and apoptosis related mRNA transcript levels were determined using real-time polymerase chain reaction (RT-PCR). Nymphayol potentially inhibits MCF-7 cell viability up to 78%, and the IC50 value was observed as 2.8 µM in 24 h and 1.4 µM in 48 h. Treatment with nymphayol significantly increased reactive oxygen species (ROS) level and the tunnel assay confirmed DNA damage. We found characteristically 76% apoptotic cells and 9% necrotic cells in PI and AO/ErBr staining after 48 h treatment with 2.8 µM of nymphayol. Gene expression analysis confirmed significantly (p ≤ 0.001) increased mRNA levels of cyclin dependent kinase inhibitor 2A (Cdkn2a), retinoblastoma protein 2 (pRb2), p53, nuclear factor erythroid 2-factor 2 (Nrf2), caspase-3, and decreased B-cell lymphoma 2 (Bcl-2), murine double minute 2 (mdm2), and proliferating cell nuclear antigen (PCNA) expression after 48 h. Nymphayol effectively inhibited breast cancer cell viability, and is associated with early expression of Cdkn2a, pRb2, and activation of p53 and caspases.

scholarly journals Integrative analysis of mRNA and miRNA profiles identifies miR-193 and miR-210 as potential regulatory biomarkers in different molecular subtypes of breast cancer

2020 ◽  
Author(s):  
Adriane Feijo Evangelista ◽  
Renato J Oliveira ◽  
Viviane A O Silva ◽  
Rene A D C Vieira ◽  
Rui M Reis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Line ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Cancer Progression ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Breast Cancer Cell Lines ◽  
Mcf 7

Abstract Introduction: Breast cancer is the most frequently diagnosed malignancy among women. However, the role of microRNA expression in breast cancer progression is not fully understood. In this study we examined predictive interactions between differentially expressed miRNAs and mRNAs in breast cancer cell lines representative of the common molecular subtypes. Integrative bioinformatics analysis identified miR-193 and miR-210 as potential regulatory biomarkers of mRNA in breast cancer. Several recent studies have investigated these miRNAs in a broad range of tumors, but the mechanism of their involvement in cancer progression has not previously been investigated. Methods: The miRNA-mRNA interactions in breast cancer cell lines were identified by parallel expression analysis and miRNA target prediction programs. The expression profiles of mRNA and miRNAs from luminal (MCF-7, MCF-7/AZ and T47D), HER2 (BT20 and SK-BR3) and triple negative subtypes (Hs578T e MDA-MB-231) could be clearly separated by unsupervised analysis using HB4A cell line as a control. Breast cancer miRNA data from TCGA patients were grouped according to molecular subtypes and then used to validate these findings. Expression of miR-193 and miR-210 was investigated by miRNA transient silencing assays using the MCF7, BT20 and MDA-MB-231 cell lines. Functional studies included, xCELLigence system, ApoTox-Glo triplex, flow cytometry and transwell assays were performed to determine cell proliferation, cytotoxicity, apoptosis, migration and invasion, respectively. Results: The most evident effects were associated with cell proliferation after miR-210 silencing in triple negative subtype cell line MDA-MB-231. Using in silico prediction algorithms, TNFRSF10 was identified as one of the potential downstream targets for both miRNAs. The TNFRSF10C and TNFRSF10D mRNA expression inversely correlated with the expression levels of miR-193 and miR210 in breast cell lines and breast cancer patients, respectively. Other potential regulated genes whose expression also inversely correlated with both miRNAs were CCND1, a mediator on invasion and metastasis, and the tumor suppressor gene RUNX3. Conclusion: In summary, our findings identify miR-193 and miR-210 as potential regulatory miRNA in different molecular subtypes of breast cancer and suggest that miR-210 may have specific role in MDA-MB-231 proliferation. Our results highlight important new downstream regulated targets that may serve as promising therapeutic pathways for aggressive breast cancers.

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