Pattern of amplification and overexpression of the eukaryotic initiation factor 4E gene in solid tumor.

BACKGROUND

An abundance of eukaryotic initiation factor 4E (eIF4E), a rate-limiting initiation component in protein synthesis of mRNAs with long 5'-UTRs, has been shown to upregulate a number of oncogene products. Elevation of eIF4E protein has been detected both in infiltrating ductal carcinoma of the breast (IDCA) and in head and neck squamous cell carcinoma (HNSCC) specimens. We hypothesized that malignant progression in solid tumor is associated with progressive eIF4E gene amplification and protein overexpression in cells sampled from the tumor-free resection margin, transition zone (area adjacent to cancer), and tumor core (center of tumor).

MATERIALS AND METHODS

Thirty-eight resected specimens were evaluated: 10 IDCA, 13 HNSCC, and 15 benign specimens from similar sites of noncancer patients. IDCA and HNSCC specimens were divided into three different zones: (1) tumor core, (2) transition zone, and (3) tumor-free zone. Quantitative PCR for the eIF4E gene and Western blots for the eIF4E protein were performed on each of these zones and on the normal controls of benign tissue. Immunohistochemical staining was performed to localize the eIF4E protein overexpression in situ.

RESULTS

The eIF4E gene was amplified in the tumor core of both IDCA (3.8 +/- 1.4, P < 0.05, Student's t test) and HNSCC (4.3 +/- 1.4, P < 0.05) specimens. Similarly, the eIF4E protein was overexpressed in the cells from these same sites (17.4 +/- 7.3- and 14.0 +/- 9.7-fold elevation, respectively, P < 0.0001). In the transition zone of IDCA and HNSCC, the degrees of eIF4E gene amplification (4.2 +/- 1.0 and 3.7 +/- 1.2, respectively) and overexpression (4.0 +/- 1.0 and 4.4 +/- 4.6, respectively) were intermediate. In contrast, the eIF4E gene copy number and protein level were near baseline in the tumor-free zone.

CONCLUSIONS

Progressive eIF4E gene amplification and protein overexpression were present in cells sampled from the microscopically tumor-free margin to tumor core in surgical specimens of both HNSCC and IDCA. In this study, eIF4E gene amplification and protein overexpression appear to be associated with malignant progression in these two solid tumors.