scholarly journals ZDHHC22-Mediated mTOR Palmitoylation Determines Breast Tumor Growth and Endocrine Therapy Sensitivity

2021 ◽  
Author(s):  
Jiefeng Huang ◽  
Jie Li ◽  
Jun Tang ◽  
Yushen Wu ◽  
Ziying Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Expression Profiles ◽  
Methylation Status ◽  
The Cancer Genome Atlas ◽  
Site Mutation ◽  
Western Blots ◽  
Tamoxifen Resistant ◽  
First Time

Abstract BackgroundPalmitoylation is essential for classic hallmarks of cancer, regulating protein stability and protein-protein interactions. Targeting palmitoylation or palmitoyltransferases has become a novel strategy for therapeutic intervention in cancer. However, few studies have reported the expression pattern, pathological functions and underlying mechanism of ZDHHC22 in breast cancer.MethodsPublic database analysis, quantitative reverse transcription PCR, and western blot were used to analyze ZDHHC22 expression. Methylation-specific PCR was employed to detect the promoter methylation status. Expression of mTOR was examined by immunofluorescence staining and western blots, and palmitoylation of mTOR was detected by acyl-biotin exchange assays. Cellular functions were evaluated via corresponding molecular biological and cellular approaches. Nude mice were used to generate a xenograft tumor model.ResultsWe investigated the expression profiles of 23 palmitoyltransferases using data from The Cancer Genome Atlas and found that ZDHHC22 is frequently expressed at minimal levels in multiple cancers. Downregulation of ZDHHC22 is associated with methylation of its promoter in breast cancer. Ectopic ZDHHC22 expression inhibits the malignant properties of breast cancer both in vitro and in vivo. The enzyme-active site-mutation ZDHHC22-(C111A) mutation reversed these effects, demonstrating that ZDHHC22 suppresses the malignant properties of breast cancer through palmitoylation. Bioinformatics analysis predicted mTOR as the substrate of ZDHHC22. mTOR palmitoylation for the first time was detected and we found ZDHHC22 reduced the stability of mTOR via regulating the palmitoylation of mTOR. Additionally, mTOR expression was frequently negatively correlated with ZDHHC22 in tamoxifen-resistant breast cancer cells and ectopic ZDHHC22 could restore endocrine sensitivity in tamoxifen-resistant breast cancer cell line.ConclusionOur results demonstrating the hypermethylated status and potential tumor suppressor function of ZDHHC22 in breast cancer for the first time established a regulatory mechanism between ZDHHC22 and mTOR palmitoylation, which may pave the way for the development of promising therapeutics that restore endocrine sensitivity.

scholarly journals Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma

2018 ◽  
Vol 129 (6) ◽  
pp. 1446-1455 ◽  
Author(s):  
Markus M. Luedi ◽  
Sanjay K. Singh ◽  
Jennifer C. Mosley ◽  
Islam S. A. Hassan ◽  
Masumeh Hatami ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Expression Profiles ◽  
Clinical Information ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Boyden Chamber ◽  
Ki 67 ◽  
Marker Selection

OBJECTIVEDexamethasone, a known regulator of mesenchymal programming in glioblastoma (GBM), is routinely used to manage edema in GBM patients. Dexamethasone also activates the expression of genes, such as CEBPB, in GBM stem cells (GSCs). However, the drug’s impact on invasion, proliferation, and angiogenesis in GBM remains unclear. To determine whether dexamethasone induces invasion, proliferation, and angiogenesis in GBM, the authors investigated the drug’s impact in vitro, in vivo, and in clinical information derived from The Cancer Genome Atlas (TCGA) cohort.METHODSExpression profiles of patients from the TCGA cohort with mesenchymal GBM (n = 155) were compared with patients with proneural GBM by comparative marker selection. To obtain robust data, GSCs with IDH1 wild-type (GSC3) and with IDH1 mutant (GSC6) status were exposed to dexamethasone in vitro and in vivo and analyzed for invasion (Boyden chamber, human-specific nucleolin), proliferation (Ki-67), and angiogenesis (CD31). Ex vivo tumor cells from dexamethasone-treated and control mice were isolated by fluorescence activated cell sorting and profiled using Affymetrix chips for mRNA (HTA 2.0) and microRNAs (miRNA 4.0). A pathway analysis was performed to identify a dexamethasone-regulated gene signature, and its relationship with overall survival (OS) was assessed using Kaplan-Meier analysis in the entire GBM TCGA cohort (n = 520).RESULTSThe mesenchymal subgroup, when compared with the proneural subgroup, had significant upregulation of a dexamethasone-regulated gene network, as well as canonical pathways of proliferation, invasion, and angiogenesis. Dexamethasone-treated GSC3 demonstrated a significant increase in invasion, both in vitro and in vivo, whereas GSC6 demonstrated a modest increase. Furthermore, dexamethasone treatment of both GSC3 and GSC6 lines resulted in significantly elevated cell proliferation and angiogenesis in vivo. Patients with mesenchymal GBM had significant upregulation of dexamethasone-regulated pathways when compared with patients with proneural GBM. A prognostic (p = 0.0007) 33-gene signature was derived from the ex vivo expression profile analyses and used to dichotomize the entire TCGA cohort by high (median OS 12.65 months) or low (median OS 14.91 months) dexamethasone signature.CONCLUSIONSThe authors present evidence that furthers the understanding of the complex effects of dexamethasone on biological characteristics of GBM. The results suggest that the drug increases invasion, proliferation, and angiogenesis in human GSC-derived orthotopic tumors, potentially worsening GBM patients’ prognoses. The authors believe that careful investigation is needed to determine how to minimize these deleterious dexamethasone-associated side effects in GBM.

Expression of ERG11 and efflux pump genes CDR1, CDR2 and SNQ2 in voriconazole susceptible and resistant Candida glabrata strains

2019 ◽  
Vol 58 (1) ◽  
pp. 30-38
Author(s):  
Patricia Navarro-Rodríguez ◽  
Adela Martin-Vicente ◽  
Loida López-Fernández ◽  
Josep Guarro ◽  
Javier Capilla
Keyword(s):  
Gene Expression ◽  
Candida Glabrata ◽  
Efflux Pump ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Clear Correlation ◽  
Synonymous Mutations ◽  
First Time

AbstractCandida glabrata causes difficult to treat invasive candidiasis due to its antifungal resistance, mainly to azoles. The aim of the present work was to study the role of the genes ERG11, CDR1, CDR2, and SNQ2 on the resistance to voriconazole (VRC) in a set of C. glabrata strains with known in vitro and in vivo susceptibility to this drug. Eighteen clinical isolates of C. glabrata were exposed in vitro to VRC, and the expression of the cited genes was quantified by real time quantitative polymerase chain reaction (q-PCR). In addition, the ERG11 gene was amplified and sequenced to detect possible mutations. Ten synonymous mutations were found in 15 strains, two of them being reported for the first time; however, no amino acid changes were detected. ERG11 and CDR1 were the most expressed genes in all the strains tested, while the expression of CDR2 and SNQ2 was modest. Our results show that gene expression does not directly correlate with the VRC MIC. In addition, the expression profiles of ERG11 and efflux pump genes did not change consistently after exposure to VRC. Although individual analysis did not result in a clear correlation between MIC and gene expression, we did observe an increase in ERG11 and CDR1 expression in resistant strains. It is of interest that considering both in vitro and in vivo results, the slight increase in such gene expression correlates with the observed resistance to VRC.

scholarly journals In VivoandIn VitroGenotoxic and Epigenetic Effects of Two Types of Cola Beverages and Caffeine: A Multiassay Approach

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Marcos Mateo-Fernández ◽  
Tania Merinas-Amo ◽  
Miguel Moreno-Millán ◽  
Ángeles Alonso-Moraga ◽  
Sebastián Demyda-Peyrás
Keyword(s):  
Biological Effects ◽  
Methylation Status ◽  
Repetitive Elements ◽  
Cytotoxic Activities ◽  
Epigenetic Effects ◽  
Chemopreventive Effect ◽  
First Time ◽  
Different Doses

The aim of this work was to assess the biological and food safety of two different beverages: Classic Coca Cola™(CCC) and Caffeine-Free Coca Cola (CFCC). To this end, we determined the genotoxicological and biological effects of different doses of lyophilised CCC and CFCC and Caffeine (CAF), the main distinctive constituent. Their toxic/antitoxic, genotoxic/antigenotoxic, and chronic toxicity (lifespan assay) effects were determinedin vivousing theDrosophilamodel. Their cytotoxic activities were determined using the HL-60in vitrocancer model. In addition, clastogenic DNA toxicity was measured using internucleosomal fragmentation and SCGE assays. Their epigenetic effects were assessed on the HL-60 methylation status using some repetitive elements. The experimental results showed a slight chemopreventive effect of the two cola beverages against HL-60 leukaemia cells, probably mediated by nonapoptotic mechanisms. Finally, CCC and CAF induced a global genome hypomethylation evaluated in LINE-1 and Alu M1 repetitive elements. Overall, we demonstrated for the first time the safety of this famous beverage inin vivoandin vitromodels.

scholarly journals Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Cui-Cui Zhao ◽  
Jing Chen ◽  
Li-Ying Zhang ◽  
Hong Liu ◽  
Chuan-Gui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
The Cancer Genome Atlas ◽  
Proliferation And Apoptosis

Abstract Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

CircPLK1 sponges miR-296-5p to facilitate triple-negative breast cancer progression

Epigenomics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1163-1176 ◽  
Author(s):  
Yanan Kong ◽  
Lu Yang ◽  
Weidong Wei ◽  
Ning Lyu ◽  
Yutian Zou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Proliferation And Metastasis ◽  
Underlying Mechanisms

Aim: To investigate the role of circRNAs in triple-negative breast cancer (TNBC) and the underlying mechanisms. Materials & methods: We performed circRNA microarrays to explore the expression profiles of TNBC cell lines. Experiments in vitro and in vivo were conducted to explore the effects of circPLK1 on tumor proliferation and metastasis as well as the interaction between circPLK1, miR-296-5p and PLK1 in TNBC. Results & conclusion: CircPLK1 was significantly upregulated in TNBC and associated with poor survivals. CircPLK1 knockdown inhibited cell growth and invasion in vitro as well as tumor occurrence and metastasis in vivo. CircPLK1-miR-296-5p- PLK1 axis regulates tumor progression by ceRNA mechanism in TNBC, indicating that circPLK1 may serve as a prognostic factor and novel therapeutic target for TNBC.

scholarly journals Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: evidence using a novel bone-seeking cell line

2014 ◽  
Vol 21 (2) ◽  
pp. 327-341 ◽  
Author(s):  
Faith Nutter ◽  
Ingunn Holen ◽  
Hannah K Brown ◽  
Simon S Cross ◽  
C Alyson Evans ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Expression Profiles ◽  
Molecular Profile ◽  
Calcium Signal ◽  
Cell Homing ◽  
Gene And Protein Expression ◽  
Breast Cancer Bone Metastasis

Advanced breast cancer is associated with the development of incurable bone metastasis. The two key processes involved, tumour cell homing to and subsequent colonisation of bone, remain to be clearly defined. Genetic studies have indicated that different genes facilitate homing and colonisation of secondary sites. To identify specific changes in gene and protein expression associated with bone-homing or colonisation, we have developed a novel bone-seeking clone of MDA-MB-231 breast cancer cells that exclusively forms tumours in long bones following i.v. injection in nude mice. Bone-homing cells were indistinguishable from parental cells in terms of growth ratein vitroand when grown subcutaneouslyin vivo. Only bone-homing ability differed between the lines; once established in bone, tumours from both lines displayed similar rates of progression and caused the same extent of lytic bone disease. By comparing the molecular profile of a panel of metastasis-associated genes, we have identified differential expression profiles associated with bone-homing or colonisation. Bone-homing cells had decreased expression of the cell adhesion molecule fibronectin and the migration and calcium signal binding protein S100A4, in addition to increased expression of interleukin 1B. Bone colonisation was associated with increased fibronectin and upregulation of molecules influencing signal transduction pathways and breakdown of extracellular matrix, including hRAS and matrix metalloproteinase 9. Our data support the hypothesis that during early stages of breast cancer bone metastasis, a specific set of genes are altered to facilitate bone-homing, and that disruption of these may be required for effective therapeutic targeting of this process.

Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol

2016 ◽  
Vol 130 (24) ◽  
pp. 2267-2276 ◽  
Author(s):  
Dong-xu He ◽  
Feng Gu ◽  
Jian Wu ◽  
Xiao-Ting Gu ◽  
Chun-Xiao Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Transforming Growth Factor Β ◽  
Clinical Samples ◽  
Breast Cancer Patients

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-β (TGF-β)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

scholarly journals The human intermediate prolactin receptor is a mammary proto-oncogene

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jacqueline M. Grible ◽  
Patricija Zot ◽  
Amy L. Olex ◽  
Shannon E. Hedrick ◽  
J. Chuck Harrell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prolactin Receptor ◽  
The Cancer Genome Atlas ◽  
Cancer Tissue ◽  
Mcf7 Cells ◽  
Cancer Pathogenesis ◽  
Cancer Genome Atlas ◽  
Alternatively Spliced

AbstractThe hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. The goal of this study was to determine if a similar transforming event occurs with the hPRLr in human breast epithelial cells and to better understand the mechanism behind such transformation. hPRLrL+I co-expression in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce Stat5a tyrosine phosphorylation. Both immunohistochemical breast cancer tissue microarray data and RNA sequencing analyses using The Cancer Genome Atlas (TCGA) identified that higher hPRLrI expression associates with triple-negative breast cancer. These studies indicate the hPRLrI, when expressed alongside hPRLrL, participates in mammary transformation, and represents a novel oncogenic mechanism.

scholarly journals Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α–Positive Feedback Loop

2021 ◽  
Vol 9 ◽  
Author(s):  
Xu Liu ◽  
Kun Qiao ◽  
Kaiyuan Zhu ◽  
Xianglan Li ◽  
Chunbo Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Noncoding Rna ◽  
Feedback Loop ◽  
Hypoxia Inducible Factor ◽  
The Cancer Genome Atlas ◽  
Positive Feedback Loop ◽  
Downstream Target

In recent years, an increasing number of studies have reported that long noncoding RNAs (lncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that lncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues compared with normal tissues in The Cancer Genome Atlas database. However, the exact biological roles of HCG18 in BC remain unclear. In this study, we demonstrated that HCG18 is significantly upregulated in BC tissues and cells and that BC patients with high HCG18 expression tend to have poor prognosis. In vitro assays indicated that HCG18 promotes BC cell proliferation and invasion and endows BC cells with cancer stemness properties. In vivo assays revealed that reducing HCG18 expression in the BC cell line MDA-MB-231 markedly decreased tumor growth and lung metastasis in xenograft mouse models. In terms of mechanism, we found that HCG18 positively regulated the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, and our previous research verified that UBE2O could promote the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of the HCG18/miR-103a-3p/UBE2O/mTORC1 axis, hypoxia-inducible factor 1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Taken together, these results confirm that HCG18 plays an oncogenic role in BC and might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.

scholarly journals Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2773 ◽  
Author(s):  
Coralie Poulard ◽  
Julien Jacquemetton ◽  
Olivier Trédan ◽  
Pascale A. Cohen ◽  
Julie Vendrell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
In Vitro Models ◽  
Proximity Ligation Assay ◽  
Breast Cancers ◽  
Cancer Management ◽  
Tamoxifen Resistant

Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα–Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.

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