Detection of eIF4E gene amplification in breast cancer by competitive PCR

Sorrells, Donald L.; Black, Destin; Meschonat, Carol; Rhoads, Robert E.; Benedetti, Arrigo De; Gao, Ming; Williams, B. Jill; Li, Benjamin D.L.

doi:10.1007/bf02303778

Cited by 55 publications

(44 citation statements)

References 14 publications

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“…The role of initiation factors in the progression to a malignant phenotype is reported in many cancers, including, breast, head and neck, liver, prostate, bladder, gastric, colon, ovarian, glioma, lymphoma, non-small cell lung carcinoma, cervical, small intestine, and melanoma (20,(23)(24)(25). This has highlighted eIFs, notably eIF4E, as indicative of poor prognosis.…”

Section: Discussionmentioning

confidence: 97%

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Humphries

Rajan

Droop

et al. 2017

Clinical Cancer Research

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Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n ¼ 477, training; n ¼ 220, validation set) and quantified in pre-and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P ¼ 0.013; HR ¼ 1.77, 1.12-2.8 and P ¼ 0.035; HR ¼ 1.68, 1.03-2.74, respectively), or when coexpressed (P ¼ 0.01; HR ¼ 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P ¼ 0.016; HR ¼ 2.38 (1.18-4.8), eIF5 P ¼ 0.022; HR ¼ 2.55 (1.14-5.7); coexpression P ¼ 0.001; HR ¼ 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.

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Section: Discussionmentioning

confidence: 97%

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Humphries

Rajan

Droop

et al. 2017

Clinical Cancer Research

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“…24,25 Inhibition of COX-2 by MEK inhibitors is unlikely to explain the cytostatic effects of the MEK inhibitors, however, because other investigators have shown that COX-2 inhibitors are cytotoxic to NSCLC cells, with and without chemotherapy. 26,27 In contrast to PD98059, nonspecific effects of DNMs toward inhibition of other targets have not been described. Future studies will determine if DNMs and small molecule MEK inhibitors have differential effects on inhibition of COX-1, COX-2, or aryl hydrocarbon receptors, and whether this contributes to the different cellular responses of NSCLC cells to inhibition of the MEK/ERK pathway by MEK inhibitors or DNMs.…”

Section: Discussionmentioning

confidence: 99%

Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

Brognard

Dennis

2002

Cell Death Differ

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To evaluate the role of the MEK/ERK pathway in NSCLC survival, we analyzed NSCLC cell lines that differed in tumor histology and status of p53, Rb, and K-ras. Constitutive ERK1/2 activity was demonstrated in 17 of 19 cell lines by maintenance of ERK1/2 phosphorylation with serum deprivation. Phosphorylation of ERK1/2 correlated with phosphorylation of MEK1/2 and p90RSK, but was inversely correlated with phosphorylation of c-Raf at S259. With serum deprivation, the MEK inhibitors, PD98059 and U0126, inhibited ERK1/2 activity but did not increase apoptosis. PD98059 and U0126 induced cell cycle arrest in G 0 /G i in cells with the highest levels of ERK1/2 activity, which correlated with induction of p27 but not p21. To confirm the cytostatic response to MEK inhibitors, we performed transient transfections with dominant negative forms of MEK or ERK. Surprisingly, dominant negative MEK and ERK mutants increased apoptosis without affecting cell cycle or p27 levels. When combined with paclitaxel, MEK inhibitors had no effect on apoptosis. In contrast, dominant negative ERK2 potentiated paclitaxel-induced apoptosis. Our studies show that constitutive ERK1/2 activity in NSCLC cells promotes cellular survival and chemotherapeutic resistance. Moreover, our data are the first to demonstrate divergent cellular responses to inhibition of the MEK/ERK pathway by small molecule inhibitors or dominant negative mutants.

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“…A, activity that can overcome the cellular barrier of apoptosis resulting from MYC-induced oncogenic stress (12,13). eIF4E gene amplification has been reported in human breast cancer and in head and neck cancer specimens compared with noncancerous control samples (14,15).…”

Section: Eif4e In Cancer Initiation and Progressionmentioning

confidence: 99%

Targeting Eukaryotic Translation Initiation Factor 4E (eIF4E) in Cancer

Hsieh

Ruggero

2010

Clinical Cancer Research

167

150

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Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action.

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Detection of eIF4E gene amplification in breast cancer by competitive PCR

Abstract: Overexpression of eIF4E was associated with eIF4E gene amplification in breast cancer specimens. No overexpression or gene amplification was detected in benign breast tissues. eIF4E gene amplification may be one mechanism for eIF4E oncoprotein overexpression.

Cited by 55 publications

References 14 publications

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

Targeting Eukaryotic Translation Initiation Factor 4E (eIF4E) in Cancer

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