Up-regulation of TLK1B by eIF4E overexpression predicts cancer recurrence in irradiated patients with breast cancer

Abstract

The overexpression of eukaryotic initiation factor 4E (eIF4E), which is a critical component of the RNA helicase complex important in the translation of messenger RNAs with long and/or complex 5' untranslated regions, appears to impact malignant transformation and predict cancer recurrence in patients with breast cancer, independent of nodal status. Tousled-like kinase (TLK1B) is a mammalian threonine kinase with a long 5' untranslated regions in the messenger RNA. In vitro, malignant cells with eIF4E overexpression appear to have corresponding TLK1B elevation. Additionally TLK1B phosphorylates histone 3, which is a protein that is involved in chromatin assembly, plays an integral role in radioresistance in cell lines. Our hypothesis is that patients with breast cancer with high eIF4E overexpression have increased TLK1B and a higher risk for recurrence after adjuvant radiation therapy. One hundred fifty-eight patients with stage I to III breast cancer were accrued in a prospective study that was designed to detect cancer recurrence in patients who had been treated with adjuvant radiation therapy. A standardized surveillance and treatment protocol was used to maximize treatment homogeneity and to detect the study primary end point, cancer recurrence. All patients received adjuvant radiation therapy either for high-risk node-positive disease or as a part of breast conservation therapy. TLK1B and eIF4E levels were quantified by Western blot. Statistical analysis was performed and included Spearman correlation, survival analysis by the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. Both eIF4E (15.4 +/- 0.6, mean +/- SD) and TLK1B (18.8 +/- 1.5) were increased in all breast cancer specimens. Increasing eIF4E overexpression was correlated highly with increasing TLK1B (r = 0.35; P < .0001, Spearman coefficient). Tertile distribution of patients, based on the degree of eIF4E and TLK1B increase, demonstrated that the patients in the highest eIF4E group and the highest TLK1B group had a higher rate of cancer recurrences (P = .015 and .049, log rank test, respectively). After adjustment for stage of disease, age, and estrogen/progesterone receptor status, data showed that patients in the highest TLK1B group had a 3.0-fold increase in relative risk for cancer recurrence after adjuvant radiation therapy (P = .036; 95% CI, 1.0-5.0), compared with patients in the low TLK1B group. The overexpression of eIF4E is correlated with TLK1B increase in cancer specimens from patients with stage I to III breast cancer. High TLK1B increase in tumor specimens was associated with a higher risk for cancer recurrence after adjuvant radiation therapy. Resistance to radiotherapy may be 1 mechanism whereby eIF4E overexpression in breast cancer portends a worse prognosis.