Clinical Outcome in Stage I to III Breast Carcinoma and eIF4E Overexpression

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Abstract
The objective of this study is to determine if high eukaryotic initiation factor 4E (eIF4E) overexpression (sevenfold elevation or more over benign breast tissue) is associated with a worse clinical outcome. Dysregulation of cellular functions by selective overexpression of specific proteins can lead to malignant transformation. The overexpression of eIF4E preferentially increases translation of mRNAs with long, G-C rich 5′-untranslated regions. Selective gene products, such as tumor neoangiogenic factors, ornithine decarboxylase, and cyclin D1, are upregulated. One hundred fourteen breast specimens were analyzed and eIF4E overexpression was quantified by Western blot analysis. Quantification for eIF4E protein level was accomplished using a rabbit anti-eIF4E antibody and colorimetric development of Western blots using nitro blue tetrazolium and 5-bromo-4-chloro-3-indolyl phosphate. The blots were scanned and analyzed by densitometry. Treatment, pathologic, and clinical outcome data variables were analyzed. Statistical analysis was performed to determine if eIF4E overexpression is associated with breast cancer clinical outcome. In the 55 benign specimens, the mean eIF4E expression was 1.1 ± 0.4 fold (mean ± standard deviation). All 59 malignant breast carcinoma specimens were noted to have eIF4E over-expression (range, 1.9-fold to 30.6-fold), with a mean overexpression of 10.8 ± 6.3-fold. The mean level of eIF4E expression in malignant specimens was higher than benign specimens (p < 0.05, unpaired t test). The degree of eIF4E overexpression appears to be independent of T and N stage. In the 21 patients with eIF4E overexpression of less than sevenfold, there was one cancer recurrence but no cancer-related deaths. In the 38 patients with high eIF4E overexpression (sevenfold or more), 14 patients had breast cancer recurrences (p = 0.03, log rank test), of whom 11 have died from the disease (p = 0.04, log rank test). The average follow-up interval in this study was 40 months. Patients with stage I to III breast cancer and high eIF4E over-expression had a higher rate of cancer recurrence and a higher rate of cancer-related death when compared to similarstage breast cancer patients with low eIF4E overexpression. Therefore, eIF4E protein overexpression may be of prognostic value in stage I to III breast carcinoma.

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