scholarly journals Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 262
Author(s):  
Patrizia Di Iorio ◽  
Maurizio Ronci ◽  
Patricia Giuliani ◽  
Francesco Caciagli ◽  
Renata Ciccarelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Targets ◽  
Second Messengers ◽  
Extracellular Signals ◽  
Intracellular Cgmp ◽  
Biological Responses ◽  
Pde Inhibitors ◽  
Regulate Cell Growth ◽  
Pros And Cons

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy.

A Fluorescence Polarization Assay for Cyclic Nucleotide Phosphodiesterases

2002 ◽  
Vol 7 (3) ◽  
pp. 215-222 ◽  
Author(s):  
Wei Huang ◽  
Yan Zhang ◽  
J. Richard Sportsman
Keyword(s):  
Cyclic Nucleotide ◽  
Fluorescence Polarization ◽  
Drug Targets ◽  
Second Messengers ◽  
Reaction Products ◽  
Cyclic Nucleotide Phosphodiesterases ◽  
Extracellular Signals ◽  
Fluorescence Polarization Assay ◽  
Hydrolysis Of ◽  
Nucleotide Phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of the 3′-ester bond of cyclic AMP (cAMP) and cyclic GMP (cGMP), important second messengers in the transduction of a variety of extracellular signals. There is growing interest in the study of PDEs as drug targets for novel therapeutics. We describe the development of a homogeneous fluorescence polarization assay for PDEs based on the strong binding of PDE reaction products (i.e., AMP or GMP) onto modified nanoparticles through interactions with immobilized trivalent metal cations. This assay technology (IMAP) is applicable to both cAMP- and cGMP-specific PDEs. Results of the assay in 384- and 1536-well microplates are presented.

scholarly journals Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Yanli Bi ◽  
Longyuan Gong ◽  
Pengyuan Liu ◽  
Xiufang Xiong ◽  
Yongchao Zhao
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Transcriptional Repression ◽  
Breast Cancer Cells ◽  
Kinase Activity ◽  
Nuclear Translocation ◽  
Extracellular Signals ◽  
Consensus Binding Sequence ◽  
Binding Sequence

AbstractErbB2, a classical receptor tyrosine kinase, is frequently overexpressed in breast cancer cells. Although the role of ErbB2 in the transmission of extracellular signals to intracellular matrix has been widely studied, the functions of nuclear ErbB2 remain largely elusive. Here, we report a novel function of nuclear ErbB2 in repressing the transcription of DEPTOR, a direct inhibitor of mTOR. Nuclear ErbB2 directly binds to the consensus binding sequence in the DEPTOR promoter to repress its transcription. The kinase activity of ErbB2 is required for its nuclear translocation and transcriptional repression of DEPTOR. Moreover, the repressed DEPTOR by nuclear ErbB2 inhibits the induction of autophagy by activating mTORC1. Thus, our study reveals a novel mechanism for autophagy regulation by functional ErbB2, which translocates to the nucleus and acts as a transcriptional regulator to suppress DEPTOR transcription, leading to activation of the PI3K/AKT/mTOR pathway to inhibit autophagy.

scholarly journals Role of Differentially Expressed Proteins in Acquired Resistance to Cdk4/6 Inhibitor in Breast Cancer

2021 ◽  
Author(s):  
Binayak Kumar ◽  
Peeyush Prasad ◽  
Ragini Singh ◽  
Ram Krishana Sahu ◽  
Ashutosh Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Targets ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Resistant Cell ◽  
Molecular Signature ◽  
Mcf 7 ◽  
Resistant Cells

Abstract CDK4/6 inhibitors (Abemaciclib, Ab and Palbociclib, Pb) stop the G1-phase in cell-cycle being used to cure advanced stage of breast cancer (BC). Acquired resistance is a major challenge in BC therapy. The molecular signature of the therapy resistance for Ab and Pb drugs in BC should be explored. Here, we developed Ab/Pb-resistant cell-models and explored the molecular changes. Drug’s resistance cells were developed in MCF-7 cells by continuous drug treatment and it was confirmed by MTT-assay, PI-staining-microscopy, and real-time-qPCR. Global proteome profiling done by Labelled-free-Proteome-Orbitrap-Fusion-MS-MS technique. Bioinformatics tools used to analyse the proteome data. Ab-resistant and Pb-resistant MCF-7 cells showed increased tolerance for the respective drug. The BCL-2 and MCL-1 survival genes were up-regulated, while the apoptosis genes BAD, BAX, CASP-3 and PARP-1were down-regulated in the resistant cells. Expression of the MDR-1, ABCG2, ESR-1, CDK4, CDK6, and Cyclin-D1 genes were increased in both resistance cells. For proteomics, 237 and 239 proteins were expressed differently in the resistant Ab and Pb cells, respectively. The NUDT5, PEPD, ABAT, ATP1B1, GGCT, and SELENBP1 proteins were down-regulated and the SBSN, HSD17B10, CD9, PDIA3, PSMB4, SLC2A1, and VTN proteins were up-regulated in Ab-resistant cells. The NUDT5, PEPD, and GGCT proteins were down-regulated, while CD47, HIST1H2BN, LMNA, VTN, PSMB5, HBB, PSMA7, FLNB, PRDX4, VDAC1, GOT2, HSPA5, SERPINH1, EIF4A2, FTH, and VIM proteins were up-regulated in Pb-resistant cells. These proteins are a new set of prognostic markers and drug targets for overcoming the respective drug resistance. However, it is necessary to perform an in vivo or clinical assessment.

scholarly journals Clinical Theragnostic Relationship between Drug-Resistance Specific miRNA Expressions, Chemotherapeutic Resistance, and Sensitivity in Breast Cancer: A Systematic Review and Meta-Analysis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1250 ◽  
Author(s):  
Jayaraj ◽  
Nayagam ◽  
Kar ◽  
Sathyakumar ◽  
Mohammed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Drug Targets ◽  
Meta Analysis ◽  
Treatment Options ◽  
Rank Correlation ◽  
P Value ◽  
Bibliographic Search ◽  
Trim And Fill

Awareness of breast cancer has been increasing due to early detection, but the advanced disease has limited treatment options. There has been growing evidence on the role of miRNAs involved in regulating the resistance in several cancers. We performed a comprehensive systematic review and meta-analysis on the role of miRNAs in influencing the chemoresistance and sensitivity of breast cancer. A bibliographic search was performed in PubMed and Science Direct based on the search strategy, and studies published until December 2018 were retrieved. The eligible studies were included based on the selection criteria, and a detailed systematic review and meta-analysis were performed based on PRISMA guidelines. A random-effects model was utilised to evaluate the combined effect size of the obtained hazard ratio and 95% confidence intervals from the eligible studies. Publication bias was assessed with Cochran’s Q test, I2 statistic, Orwin and Classic fail-safe N test, Begg and Mazumdar rank correlation test, Duval and Tweedie trim and fill calculation and the Egger’s bias indicator. A total of 4584 potential studies were screened. Of these, 85 articles were eligible for our systematic review and meta-analysis. In the 85 studies, 188 different miRNAs were studied, of which 96 were upregulated, 87 were downregulated and 5 were not involved in regulation. Overall, 24 drugs were used for treatment, with doxorubicin being prominently reported in 15 studies followed by Paclitaxel in 11 studies, and 5 drugs were used in combinations. We found only two significant HR values from the studies (miR-125b and miR-4443) and our meta-analysis results yielded a combined HR value of 0.748 with a 95% confidence interval of 0.508–1.100; p-value of 0.140. In conclusion, our results suggest there are different miRNAs involved in the regulation of chemoresistance through diverse drug genetic targets. These biomarkers play a crucial role in guiding the effective diagnostic and prognostic efficiency of breast cancer. The screening of miRNAs as a theragnostic biomarker must be brought into regular practice for all diseases. We anticipate that our study serves as a reference in framing future studies and clinical trials for utilising miRNAs and their respective drug targets.

scholarly journals Breast Cancer Biology: The Multifaceted Roles of Mesenchymal Stem Cells

2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Shyam A. Patel ◽  
Andrew C. Heinrich ◽  
Bobby Y. Reddy ◽  
Balaji Srinivas ◽  
Nicole Heidaran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Biology ◽  
Drug Targets ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Growth Factor Signaling ◽  
Growth Factor Signaling Pathway

Recent upsurge in the interest of breast cancer metastasis is partly attributed to the discovery of novel, yet unclear, mechanisms of breast cancer interaction with sites of distant metastasis such as the bone marrow microenvironment. In this review, we discuss the significance of the interactions between breast cancer cells and cells of the bone marrow. This is a subject of intense research studies aim to provide new methods of treatments and perhaps the identification of new drug targets. This review also discusses the role of inflammation and the bimodal function of the transforming growth factor- signaling pathway in the process of tumorigenesis. We bring attention to future prospects in breast cancer research, including the role of microRNAs in cancer quiescence in the bone marrow and the application of microRNAs to basic science discoveries in oncology. Finally, we discuss the cancer stem cell hypothesis, which is not a new idea, but has resurged with investigative questions.

scholarly journals Role of sphingolipids in oestrogen signalling in breast cancer cells: an update

2013 ◽  
Vol 220 (3) ◽  
pp. R25-R35 ◽  
Author(s):  
O Sukocheva ◽  
C Wadham
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Second Messengers ◽  
Membrane Receptors ◽  
Future Research ◽  
Specific Effects ◽  
Oestrogen Signalling ◽  
Signalling Cascade

The signaling pathways activated by the steroid hormone oestrogen include a variety of cytoplasmic second messengers linked to a multitude of tissue-specific effects. In the last decade, sphingolipids and their membrane receptors were added to the list of oestrogen-activated mediators. Oestrogen triggers the sphingolipid signalling cascade in various tissues including breast cancer. Extensive research has shown that sphingolipids are the key regulatory molecules in growth factor networks. Sphingolipids can control the rate of cell proliferation and the differentiation outcome during malignant transformation. In this study, we summarise novel experimental evidences linking sphingolipids to oestrogen-activated effects, highlight the role of sphingolipids in cancer cells and discuss new avenues for future research at the intersection between oestrogen and sphingolipid signalling.

scholarly journals Genome-scale meta-analysis of breast cancer datasets identifies promising targets for drug development

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Reem Altaf ◽  
Humaira Nadeem ◽  
Mustafeez Mujtaba Babar ◽  
Umair Ilyas ◽  
Syed Aun Muhammad
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Pathway Analysis ◽  
Drug Targets ◽  
Breast Cancer Progression ◽  
Therapeutic Options ◽  
Mirna Targets ◽  
Signature Genes

Abstract Background Because of the highly heterogeneous nature of breast cancer, each subtype differs in response to several treatment regimens. This has limited the therapeutic options for metastatic breast cancer disease requiring exploration of diverse therapeutic models to target tumor specific biomarkers. Methods Differentially expressed breast cancer genes identified through extensive data mapping were studied for their interaction with other target proteins involved in breast cancer progression. The molecular mechanisms by which these signature genes are involved in breast cancer metastasis were also studied through pathway analysis. The potential drug targets for these genes were also identified. Results From 50 DEGs, 20 genes were identified based on fold change and p-value and the data curation of these genes helped in shortlisting 8 potential gene signatures that can be used as potential candidates for breast cancer. Their network and pathway analysis clarified the role of these genes in breast cancer and their interaction with other signaling pathways involved in the progression of disease metastasis. The miRNA targets identified through miRDB predictor provided potential miRNA targets for these genes that can be involved in breast cancer progression. Several FDA approved drug targets were identified for the signature genes easing the therapeutic options for breast cancer treatment. Conclusion The study provides a more clarified role of signature genes, their interaction with other genes as well as signaling pathways. The miRNA prediction and the potential drugs identified will aid in assessing the role of these targets in breast cancer.

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