scholarly journals Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth

2018 ◽  
Vol 115 (31) ◽  
pp. 7949-7954 ◽  
Author(s):  
Chunyan Ren ◽  
Guangtao Zhang ◽  
Fangbin Han ◽  
Shibo Fu ◽  
Yingdi Cao ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Transcriptional Activity ◽  
Therapeutic Strategy ◽  
Triple Negative ◽  
Cell Cycle Control ◽  
Damage Repair ◽  
Bet Inhibitors ◽  
Chemical Modulation ◽  
Bet Protein ◽  
Transcription Enhancer

The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.

scholarly journals Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1246
Author(s):  
Marta Sanz-Álvarez ◽  
Ion Cristóbal ◽  
Melani Luque ◽  
Andrea Santos ◽  
Sandra Zazo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Molecular Target ◽  
Prognostic Impact ◽  
Breast Cancer Patients ◽  
Bet Inhibitors ◽  
Brd4 Inhibition ◽  
Bet Protein

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

Dihydrotestosterone induces chemo-resistance of triple-negative breast MDA-MB-231 cancer cells towards doxorubicin independent of ABCG2 and miR-328-3p

2021 ◽  
Vol 14 ◽  
Author(s):  
Bayan Al-Momany ◽  
Hana Hammad ◽  
Mamoun Ahram
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Drug Response ◽  
Therapeutic Strategy ◽  
Triple Negative ◽  
Model System ◽  
Cell Resistance ◽  
Protein Levels ◽  
Abcg2 Protein ◽  
Mcf 7

Background: Androgens potentially have an important role in the biology of breast cancer, particularly triple-negative breast cancer (TNBC). Androgen receptor (AR) may offer a novel therapeutic strategy including the use of microRNA (miRNA) molecules. We have previously shown that AR agonist, dihydrotestosterone (DHT), increases the expression of miR-328-3p in the TNBC MDA-MB-231 cells. One target of the latter miRNA is ATP-binding cassette subfamily G member 2 (ABCG2), which modulates the chemo-response of cancer cells by pumping out xenobiotics. Objective: Using MDA-MB-231 cells as a model system for TNBC, we hypothesized that DHT would induce cell sensitivity towards doxorubicin via increasing levels of miR-328-3p and, consequently, reducing ABCG2 levels. Methods: Chemo-response of cells towards doxorubicin, tamoxifen, and mitoxantrone was evaluated using cell viability MTT assay. Cells were transfected with both miR-328-3p mimic or antisense molecules. Real-time PCR was utilized to assess RNA levels and immunoblotting was performed to investigate levels of ABCG2 protein. PCR arrays were used to assess changes in the expression of drug response regulatory genes. Results: Contrary to our hypothesis, treating MDA-MB-231 cells with DHT, no effect towards tamoxifen or mitoxantrone and increased cell resistance towards doxorubicin were noted, concomitant with decreased expression of ABCG2. This under-expression of ABCG2 was also found in MCF-7 and MDA-MB-453 cells treated with DHT. Although miR-328-3p decreased ABCG2 mRNA and protein levels, the miRNA did not alter the chemo-response of cells towards doxorubicin and did not affect DHT-induced chemo-resistance. AR activation slightly decreased the expression of 5 genes, including insulin-like growth factor 1 receptor, that may explain the mechanism of DHT-induced chemo-resistance of cells. Conclusion: DHT regulates chemo-response via a mechanism independent of ABCG2 and miR-328-3p.

scholarly journals Cohesin mutations are synthetic lethal with stimulation of WNT signaling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chue Vin Chin ◽  
Jisha Antony ◽  
Sarada Ketharnathan ◽  
Anastasia Labudina ◽  
Gregory Gimenez ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Therapeutic Strategy ◽  
Synthetic Lethality ◽  
Mcf10a Cell ◽  
Synthetic Lethal ◽  
Deletion Mutations ◽  
Damage Repair ◽  
Genes Encoding ◽  
Mutant Cells ◽  
Gsk3 Inhibitor

Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21, and STAG2 and screened for synthetic lethality with 3009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin-mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunits stag2b and rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin-mutant cancers.

Proteolysis-targeting chimeras mediate the degradation of bromodomain and extra-terminal domain proteins

2020 ◽  
Vol 12 (18) ◽  
pp. 1669-1683
Author(s):  
Yifei Yang ◽  
Zhenwei Wu ◽  
Pan Chen ◽  
Peiyuan Zheng ◽  
Huibin Zhang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Drug Discovery And Development ◽  
Terminal Domain ◽  
Super Enhancer ◽  
Bet Inhibitors ◽  
Subsequent Degradation ◽  
Bet Protein

Bromodomain and extra-terminal domain (BET) protein family plays an important role in regulating gene transcription preferentially at super-enhancer regions and has been involved with several types of cancers as a candidate. Up to now, there are 16 pan-BET inhibitors in clinical trials, however, most of them have undesirable off-target and side-effects. The proteolysis-targeting chimeras technology through a heterobifunctional molecule to link the target protein and E3 ubiquitin ligase, causes the target’s ubiquitination and subsequent degradation. By using this technology, the heterobifunctional small-molecule BET degraders can induce BET protein degradation. In this review, we discuss the advances in the drug discovery and development of BET-targeting proteolysis-targeting chimeras.

scholarly journals Role of BET Inhibitors in Triple Negative Breast Cancers

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 784 ◽  
Author(s):  
Durga Khandekar ◽  
Venkataswarup Tiriveedhi
Keyword(s):  
Triple Negative ◽  
Preliminary Evidence ◽  
Special Focus ◽  
Solid Organ ◽  
Breast Cancers ◽  
Over Expression ◽  
Expression Of Genes ◽  
Cancer Models ◽  
Bet Inhibitors

Bromodomain and extraterminal domain (BET) proteins have evolved as key multifunctional super-regulators that control gene expression. These proteins have been shown to upregulate transcriptional machinery leading to over expression of genes involved in cell proliferation and carcinogenesis. Based on favorable preclinical evidence of BET inhibitors in various cancer models; currently, 26 clinical trials are underway in various stages of study on various hematological and solid organ cancers. Unfortunately, preliminary evidence for these clinical studies does not support the application of BET inhibitors as monotherapy in cancer treatment. Furthermore, the combinatorial efficiency of BET inhibitors with other chemo-and immunotherapeutic agents remain elusive. In this review, we will provide a concise summary of the molecular basis and preliminary clinical outcomes of BET inhibitors in cancer therapy, with special focus on triple negative breast cancer.

scholarly journals Nucleophosmin in Its Interaction with Ligands

2020 ◽  
Vol 21 (14) ◽  
pp. 4885
Author(s):  
Ilaria Cela ◽  
Adele Di Matteo ◽  
Luca Federici
Keyword(s):  
Nucleic Acids ◽  
Cellular Response ◽  
Therapeutic Strategy ◽  
Cell Cycle Control ◽  
Dyskeratosis Congenita ◽  
Structural Basis ◽  
Binding Partners ◽  
Nucleolar Organization ◽  
Hematological Cancers

Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.

IGFBP-3 interacts with NONO and SFPQ in PARP-dependent DNA damage repair in triple-negative breast cancer

2019 ◽  
Vol 76 (10) ◽  
pp. 2015-2030 ◽  
Author(s):  
Hasanthi C. de Silva ◽  
Mike Z. Lin ◽  
Leo Phillips ◽  
Janet L. Martin ◽  
Robert C. Baxter
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Igfbp 3
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