Fluorescence in situ hybridization analysis of c‐myc amplification in stage T3N0M0 prostate cancer in Japanese patients

Sato, Hirotaka; Minei, Sadatsugu; Hachiya, Takahiko; Yoshida, Toshio; Takimoto, Yukie

doi:10.1111/j.1442-2042.2006.01399.x

Cited by 40 publications

(26 citation statements)

References 18 publications

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“…Importantly, Myc overexpression also correlates with poor prognosis and decreased survival in a broad range of cancers (2)(3)(4)(5). However, therapeutic approaches to directly target Myc oncogenic activity are not currently available in the clinic (6).…”

Section: Neurosciencementioning

confidence: 99%

Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Pourdehnad

Truitt

Siddiqi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

225

213

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Myc is one of the most commonly deregulated oncogenes in human cancer, yet therapies directly targeting Myc hyperactivation are not presently available in the clinic. The evolutionarily conserved function of Myc in modulating protein synthesis control is critical to the Myc oncogenic program. Indeed, enhancing the protein synthesis capacity of cancer cells directly contributes to their survival, proliferation, and genome instability. Therefore, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of Myc-dependent human cancers. However, components of the translation machinery that can be exploited as therapeutic targets for Myc-driven cancers remain poorly defined. Here, we uncover a surprising and important functional link between Myc and mammalian target of rapamycin (mTOR)-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 (4EBP1), a master regulator of protein synthesis control. Using a pharmacogenetic approach, we find that mTOR-dependent phosphorylation of 4EBP1 is required for cancer cell survival in Myc-dependent tumor initiation and maintenance. We further show that a clinical mTOR active site inhibitor, which is capable of blocking mTOR-dependent 4EBP1 phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological cancers. Additionally, we demonstrate the clinical implications of these results by delineating a significant link between Myc and mTOR-dependent phosphorylation of 4EBP1 and therapeutic response in human lymphomas. Together, these findings reveal that an important mTOR substrate is found hyperactivated downstream of Myc oncogenic activity to promote tumor survival and confers synthetic lethality, thereby revealing a unique therapeutic approach to render Myc druggable in the clinic.

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Section: Neurosciencementioning

confidence: 99%

Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Pourdehnad

Truitt

Siddiqi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

225

213

View full text Add to dashboard Cite

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“…The c-MYC gene, a well-known regulator of cell proliferation and programmed cell death, maps to this region and is overrepresented in prostate carcinoma with metastases (12). Moreover, the frequency of overrepresentation of the 8q24 locus in fluorescence in situ hybridization studies increases from prostate intraepithelial neoplasia to invasive primary carcinoma (13) and was associated with poor survival (14). However, no association between SNPs in the MYC gene (263 kb from rs1447295 in the telomeric direction) and prostate cancer risk was observed in our population (9).…”

Section: Discussionmentioning

confidence: 99%

Effect of Genetic Variability within 8q24 on Aggressiveness Patterns at Diagnosis and Familial Status of Prostate Cancer

Cussenot

Azzouzi

Bantsimba-Malanda

et al. 2008

Clinical Cancer Research

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Purpose: Recently, two independent loci located at 8q24 that contribute to prostate cancer risk in men of European origin were identified. Experimental Design: Using Bayesian probability network and logistic regression model, we searched for associations between 34 single-nucleotide polymorphisms (SNP) located at 8q24 and the aggressiveness patterns of prostate adenocarcinoma or familial history of cancers in 823 White Caucasian French men. Results: Probability network according to the Markov chain algorithm separated the SNPs into two main groups: The first one was linked to the locus marked by rs6983267 and the second one was linked to the locus marked by rs1447295. When the patients were stratified according to tumor stage and prostate-specific antigen value, the association between the variant genotypes from six SNPs located in the second network and prostate cancer risk was strongest or confined to the patients from the more aggressive classes. However, the association between prostate cancer risk and the CC genotype of rs7841264, which marked the recombination hotspot at 8q24, was confined to patients with the highest Gleason score (odds ratio, 2.15; 95% confidence interval, 1.27-3.64; P = 0.004). Interestingly, the G allele of rs6983267 was associated with familial prostate cancer risk. Conclusions: Our data further support that variability at 8q24 is associated with a high risk of aggressive prostate cancer at diagnosis and is linked with familial history of prostate cancer.These results corroborate that 8q24 SNPs must be evaluated in terms of prostate cancer aggressiveness markers to optimize early diagnosis procedures and management of the disease.

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“…4). The importance of c-MYC for prostate cancer has been previously documented (38)(39)(40)(41). Taken together, these results suggest that OGT activity integrates metabolic flux to regulate the stability of c-MYC (Fig.…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

et al. 2013

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Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked b-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n ¼ 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n ¼ 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells. Cancer Res; 73(16); 5277-87. Ó2013 AACR.

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Fluorescence in situ hybridization analysis of c‐myc amplification in stage T₃N₀M₀ prostate cancer in Japanese patients

Cited by 40 publications

References 18 publications

Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Effect of Genetic Variability within 8q24 on Aggressiveness Patterns at Diagnosis and Familial Status of Prostate Cancer

O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

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