CLINICAL OUTCOME IN STAGE-I TO III BREAST-CARCINOMA AND EIF4E OVEREXPRESSION

Objective The objective of this study is to determine if high eukaryot ic initiation factor 4E (elF4E) overexpression (sevenfold elevation or more over benign breast tissue) is associated with a worse clinical o utcome. Summary Background Data Dysregulation of cellular functions by selective overexpression of specific proteins can lead to malignant t ransformation. The overexpression of elF4E preferentially increases tr anslation of mRNAs with long, G-C rich 5'-untranslated regions. Select ive gene products, such as tumor neoangiogenic factors, ornithine deca rboxylase, and cyclin D1, are upregulated. Methods One hundred fourtee n breast specimens were analyzed and elF4E overexpression was quantifi ed by Western blot analysis. Quantification for elF4E protein level wa s accomplished using a rabbit anti-elF4E antibody and colorimetric dev elopment of Western blots using nitro blue tetrazolium and 5-bromo-4-c hloro-3-indolyl phosphate. The blots were scanned and analyzed by dens itometry. Treatment, pathologic, and clinical outcome data variables w ere analyzed. Statistical analysis was performed to determine if elF4E overexpression is associated with breast cancer clinical outcome. Res ults In the 55 benign specimens, the mean elF4E expression was 1.1 +/- 0.4 fold (mean +/- standard deviation). All 59 malignant breast carci noma specimens were noted to have elF4E overexpression (range, 1.9-fol d to 30.6-fold), with a mean overexpression of 10.8 +/- 6.3-fold. The mean level of elF4E expression in malignant specimens was higher than benign specimens (p < 0.05, unpaired t test). The degree of elF4E over expression appears to be independent of T and N stage. In the 21 patie nts with elF4E overexpression of less than sevenfold, there was one ca ncer recurrence but no cancer-related deaths. In the 38 patients with high elF4E overexpression (sevenfold or more), 14 patients had breast cancer recurrences (p = 0.03, log rank test), of whom 11 have died fro m the disease (p = 0.04, log rank test), The average follow-up interva l in this study was 40 months. Conclusions Patients with stage I to II I breast cancer and high elF4E overexpression had a higher rate of can cer recurrence and a higher rate of cancer-related death when compared to similar-stage breast cancer patients with low elF4E overexpression . Therefore, elF4E protein overexpression may be of prognostic value i n stage I to III breast carcinoma.