PP2A as the Main Node of Therapeutic Strategies and Resistance Reversal in Triple-Negative Breast Cancer

Zhao, Henan; Li, Duojiao; Zhang, Baojing; Yan, Qi; Diao, Yun-Peng; Zhen, Yuhong; Shu, Xiaohong

doi:10.3390/molecules22122277

Cited by 12 publications

(7 citation statements)

References 155 publications

(190 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PP2A hyperphosphorylation, as well as upregulation of the endogenous PP2A inhibitors such as SET, has been reported as main molecular mechanisms of PP2A inhibition in many tumors including breast cancer. These alterations have progressively emerged as promising therapeutic targets in this disease [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Although it has been recently reported that PP2A inhibition is a frequent alteration in breast cancer related with poor outcome and therapy resistance, such studies have been carried out in cohorts including cases with different molecular subtypes [ 40 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

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

Sanz-Álvarez

Cristóbal

Luque

et al. 2021

Cancers

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Sanz-Álvarez

Cristóbal

Luque

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…PPP2R2B belongs to the phosphatase family, and they are involved in several biological processes. Previous reports have shown that PP2A can activate Tcell responses by inhibiting cytotoxic T-lymphocyte-associated (CTLA)-4 function or impairing programmed death-ligand (PD-L)-1 expression [25]. The PPP2R2B gene can encode the regulatory subunit B55β, forming the PP2A-B55β complex by binding to the scaffolding and catalytic subunits.…”

Section: Chromosome 5q32 and 11p12mentioning

confidence: 99%

Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population

Shen

Khatri

Rananaware

et al. 2022

Preprint

View full text Add to dashboard Cite

COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The severity of COVID-19 is highly variable and related to known (e.g., age, obesity, immune deficiency) and unknown risk factors. The widespread clinical symptoms encompass a large group of asymptomatic COVID-19 patients, raising a crucial question regarding genetic susceptibility, e.g., whether individual differences in immunity play a role in patient symptomatology and how much human leukocyte antigen (HLA) contributes to this. To reveal genetic determinants of susceptibility to COVID-19 severity in the population and further explore potential immune-related factors, we performed a genome-wide association study on 284 confirmed COVID-19 patients (cases) and 95 healthy individuals (controls). We compared cases and controls of European (EUR) ancestry and African American (AFR) ancestry separately. We identified two loci on chromosomes 5q32 and 11p12, which reach the significance threshold of suggestive association (p<1x10-5 threshold adjusted for multiple trait testing) and are associated with the COVID-19 susceptibility in the European ancestry (index rs17448496: odds ratio [OR] = 0.173; 95% confidence interval [CI], 0.08–0.36 for G allele; p=5.15× 10-5 and index rs768632395: OR = 0.166; 95% CI, 0.07–0.35 for A allele; p= 4.25×10-6, respectively), which were associated with two genes, PPP2R2B at 5q32, and LRRC4C at 11p12, respectively. To explore the linkage between HLA and COVID-19 severity, we applied fine-mapping analysis to dissect the HLA association with mild and severe cases. Using In-silico binding predictions to map the binding of risk/protective HLA to the viral structural proteins, we found the differential presentation of viral peptides in both ancestries. Lastly, extrapolation of the identified HLA from the cohort to the worldwide population revealed notable correlations. The study uncovers possible differences in susceptibility to COVID-19 in different ancestral origins in the genetic background, which may provide new insights into the pathogenesis and clinical treatment of the disease.

show abstract

“…Inhibition of PP2A has been associated with poor prognosis of breast cancer [62]. PP2A regulates the expression of estrogen receptor (ER), a key molecular determinant of breast cancer status and survival [62,63]. PP2A activation was raised as an effective treatment target in MCF-7 breast cancer cell line through its mediation of ERα expression via modulating ER mRNA stability [64].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

New Cytotoxic Cerebrosides from the Red Sea Cucumber Holothuria spinifera Supported by In-Silico Studies

et al. 2020

View full text Add to dashboard Cite

Bioactivity-guided fractionation of a methanolic extract of the Red Sea cucumber Holothuria spinifera and LC-HRESIMS-assisted dereplication resulted in the isolation of four compounds, three new cerebrosides, spiniferosides A (1), B (2), and C (3), and cholesterol sulfate (4). The chemical structures of the isolated compounds were established on the basis of their 1D NMR and HRMS spectral data. Metabolic profiling of the H. spinifera extract indicated the presence of diverse secondary metabolites, mostly hydroxy fatty acids, diterpenes, triterpenes, and cerebrosides. The isolated compounds were tested for their in vitro cytotoxicities against the breast adenocarcinoma MCF-7 cell line. Compounds 1, 2, 3, and 4 displayed promising cytotoxic activities against MCF-7 cells, with IC50 values of 13.83, 8.13, 8.27, and 35.56 µM, respectively, compared to that of the standard drug doxorubicin (IC50 8.64 µM). Additionally, docking studies were performed for compounds 1, 2, 3, and 4 to elucidate their binding interactions with the active site of the SET protein, an inhibitor of protein phosphatase 2A (PP2A), which could explain their cytotoxic activity. This study highlights the important role of these metabolites in the defense mechanism of the sea cucumber against fouling organisms and the potential uses of these active molecules in the design of new anticancer agents.

show abstract

PP2A as the Main Node of Therapeutic Strategies and Resistance Reversal in Triple-Negative Breast Cancer

Cited by 12 publications

References 155 publications

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

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

Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population

New Cytotoxic Cerebrosides from the Red Sea Cucumber Holothuria spinifera Supported by In-Silico Studies

Contact Info

Product

Resources

About