A prospective trial on initiation factor 4E (eIF4E) overexpression and cancer recurrence in node-positive breast cancer.

OBJECTIVE: A previous study of patients with stage I to III breast cancer showed that those patients whose tumors were in the highest tertile of eIF4E overexpression experienced a higher risk for recurrence. This study was designed to determine whether high eIF4E overexpression predicts cancer recurrence independent of nodal status by specifically targeting patients with node-positive disease. METHODS: The prospective trial was designed to accrue 168 patients with node-positive breast cancer to detect a 2.5-fold increase in risk for recurrence. eIF4E level was quantified by Western blots as x-fold elevated compared with breast tissues from noncancer patients. End points measured were disease recurrence and cancer-related death. Statistical analyses performed include survival analysis by the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. RESULTS: One hundred seventy-four patients with node-positive breast cancer were accrued. All patients fulfilled study inclusion and exclusion criteria, treatment protocol, and surveillance requirements, with a compliance rate >95%. The mean eIF4E elevation was 11.0 +/- 7.0-fold (range, 1.4-34.3-fold). Based on previously published data, tertile distribution was as follow: 1) lowest tertile (<7.5-fold) = 67 patients, 2) intermediate tertile (7.5-14-fold) = 54 patients, and 3) highest tertile (>14-fold) = 53 patients. At a median follow up of 32 months, patients with the highest tertile had a statistically significant higher cancer recurrence rate (log-rank test, P = 0.002) and cancer-related death rate (P = 0.036) than the lowest group. Relative risk calculations demonstrated that high eIF4E patients had a 2.4-fold increase in relative risk increase for cancer recurrence (95% confidence interval, 1.2-4.1; P = 0.01). CONCLUSIONS: In this prospective study designed to specifically address risk for recurrence in patients with node-positive breast cancer, the patients whose tumors were in the highest tertile of eIF4E overexpression had a 2.4-fold increase in relative risk for cancer recurrence. Therefore, eIF4E overexpression appears to be an independent predictor of a worse outcome in patients with breast cancer independent of nodal status.

TLK1B is elevated with eIF4E overexpression in breast cancer.

INTRODUCTION: The overexpression of eukaryotic initiation factor 4E (eIF4E), a critical component of the "RNA helicase" necessary for the initiation of protein synthesis of mRNAs with long 5' prime untranslated regions (5'UTRs), can result in malignant transformation. In a prospective study on breast cancer outcome of women with stage I to III disease, eIF4E overexpression was an independent predictor of cancer recurrence (RR = 7.3, CI = 1.58-33.9). Dysregulation of Tousled-like kinase 1B (TLK1B), a threonine kinase with a highly conserved gene sequence, has been linked to defects in cell division and DNA replication. In cell lines, TLK1B overexpression has been recently associated with resistance to radiation. The 5'UTR of TLK1B is long (1088 nt) and the structure is complex. Our hypothesis is that TLK1B elevation is correlated with the overexpression of eIF4E in human breast carcinoma. MATERIAL AND METHODS: Eighty-seven patients with invasive breast cancer and 11 patients with benign breast disease were accrued prospectively. Clinical data collected include age, race, stage, grade of tumor, ER, and PR status. TLK1B and eIF4E levels were quantified by Western blot analysis. Statistical analysis was performed using Spearman correlation, paired and unpaired t test, and multivariate analysis. RESULTS: In the 87 cancer specimens from patients with breast carcinoma, eIF4E level was elevated by a mean of 9.5-fold (range = 1.8-48.4), and TLK1B was elevated by a mean of 9.4-fold (range = 1.0-58.0) when compared to the 11 specimens from noncancer patients. Multivariate analysis performed demonstrates the degree of eIF4E overexpression is independent of age, race, tumor grade, and ER or PR status of the tumor. Similarly, the degree of TLK1B elevation is independent of age, tumor grade, and ER or PR status of the tumor. Using the Spearman correlation, the degree of TLK1B elevation was strongly correlated with the degree of eIF4E overexpression (r = 0.39, P = 0.001). CONCLUSIONS: Both eIF4E and TLK1B are elevated in breast cancer specimens but not in benign breast specimens from noncancer patients. The degree of TLK1B elevation is correlated with the degree of IF4E overexpression. Both eIF4E and TLK1B overexpression are independent of tumor grade, tumor stage, and ER and PR status.