The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor

Karlin, Kristen L.; Mondal, Gourish; Hartman, Jessica K.; Tyagi, Siddhartha; Kurley, Sarah J.; Bland, Chris; Hsu, Tiffany; Renwick, Alexander; Fang, Justin E.; Migliaccio, Ilenia; Callaway, Celetta; Nair, Amritha; Dominguez-Vidaña, Rocio; Nguyen, Don X.; Osborne, C. Kent; Schiff, Rachel; Yu-Lee, Li-Yuan; Jung, Sung Yun; Edwards, Dean P.; Hilsenbeck, Susan G.; Rosen, Jeffrey M.; Zhang, Xiang H.-F.; Shaw, Chad A.; Couch, Fergus J.; Westbrook, Thomas F.

doi:10.1016/j.celrep.2014.10.011

Cited by 26 publications

(28 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RUNX proteins regulate gene expression by functioning as molecular scaffolds to recruit chromatin remodeling enzymes (e.g., SWI/SNF and CTCF) and modulate promoter accessibility (Young et al 2007;Wu et al 2014). Studies involving the role of RUNX2 in breast cancer have demonstrated the importance of overexpression of RUNX2 in regulating tumor growth, epithelial-mesenchymal transition, and metastasis (Pratap et al 2009;Chimge et al 2011;Karlin et al 2014). Furthermore, RUNX2 has been shown to regulate the expression of genes involved in WNT/β-catenin and TGF-β signaling-two key pathways known to be dysregulated in many cancers, particularly breast cancer (Chimge and Frenkel 2013;Ferrari et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

et al. 2017

View full text Add to dashboard Cite

The majority of breast cancers expresses the estrogen receptor (ER) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER breast cancer through selective mRNA translational reprogramming.

show abstract

Section: Discussionmentioning

confidence: 99%

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Some other tumor suppressors such as CHK2 [71], BRCA1/2 [72], [73], [74], [75], ATM [76] and ATR [77], BUB1B [78], [79], CYLD [80], REST [81], and TSC1/2 [82], [83] all have been shown to interact with PLK1 . The imbalance between these interactions for regulating proliferation could be a leading cause of cancer.…”

Section: Plk1 and Human Cancermentioning

confidence: 99%

PLK1, A Potential Target for Cancer Therapy

Liu

Sun

Wang

2017

Translational Oncology

362

269

View full text Add to dashboard Cite

Polo-like kinase 1 (PLK1) plays an important role in the initiation, maintenance, and completion of mitosis. Dysfunction of PLK1 may promote cancerous transformation and drive its progression. PLK1 overexpression has been found in a variety of human cancers and was associated with poor prognoses in cancers. Many studies have showed that inhibition of PLK1 could lead to death of cancer cells by interfering with multiple stages of mitosis. Thus, PLK1 is expected to be a potential target for cancer therapy. In this article, we examined PLK1’s structural characteristics, its regulatory roles in cell mitosis, PLK1 expression, and its association with survival prognoses of cancer patients in a wide variety of cancer types, PLK1 interaction networks, and PLK1 inhibitors under investigation. Finally, we discussed the key issues in the development of PLK1-targeted cancer therapy.

show abstract

“…Again, our results inspire further research on this gene. Testis-expressed gene 14 (Tex14) is a gene encoding a preferentially expressed protein kinase and promotes the survival of breast cancer [34]. DMRT1 gene is a candidate regulator of sexual development in vertebrates and encodes conserved transcription factor essential for gonadal function.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways Associated with RUNX1 Mutations in Acute Myeloid Leukemia Using Bioinformatics Analysis

Zhu

Huang

et al. 2018

Med Sci Monit

View full text Add to dashboard Cite

Background:RUNXl plays a key regulatory role in the process of hematopoiesis and is a common target for multiple chromosomal translocations in human acute leukemia. Mutations of RUNX1 gene can lead to acute leukemia and affect the prognosis of AML patients. We aimed to identify pivotal genes and pathways involved in RUNX1mutated patients of with acute myeloid leukemia (AML) and to explore possible molecular markers for novel therapeutic targets of the disease. Material/Methods:The RNA sequencing datasets of 151 cases of AML were obtained from the Cancer Genome Atlas database. Differentially expressed genes (DEGs) were identified using edgeR of the R platform. PPI (protein-protein interaction) network clustering modules were analyzed with ClusterONE, and the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses for modules were performed. Results:A total of 379 genes were identified as DEGs. The KEGG enrichment analysis of DEGs showed significantly enriched pathways in cancer, extracellular matrix (ECM)-receptor interaction pathway, and cyclic adenosine monophosphate (cAMP) signaling pathway. The top 10 genes ranked by degree were PRKACG, ANKRD7, RNFL7, ROPN11, TEX14, PRMT8, OTOA, CFAP99, NRXN1, and DMRT1, which were identified as hub genes from the protein-protein interaction network (PPI). Statistical analysis revealed that RUNX1-mutated patients with AML had a shorter median survival time (MST) with poor clinical outcome and an increased risk of death when compared with those without RUNX1 mutations. Conclusions:DEGs and pathways identified in the present study will help understand the molecular mechanisms underlying RUNX1 mutations in AML and develop effective therapeutic strategies for RUNX1-mutation AML.

show abstract

The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor

Cited by 26 publications

References 53 publications

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

PLK1, A Potential Target for Cancer Therapy

Identification of Key Genes and Pathways Associated with RUNX1 Mutations in Acute Myeloid Leukemia Using Bioinformatics Analysis

Contact Info

Product

Resources

About