Correlation of TLK1B in elevation and recurrence in doxorubicin-treated breast cancer patients with high eIF4E overexpression.
BACKGROUND
Tousled-like kinase 1B (TLK1B), a mammalian threonine kinase, facilitates the repair of DNA breaks. Eukaryotic initiation factor 4E (eIF4E) overexpression leads to the upregulation of TLK1B. Doxorubicin, commonly used in the adjuvant setting for breast cancer, causes DNA breaks. We hypothesized that the degree of TLK1B elevation is correlated with eIF4E overexpression and translates clinically to an increased risk for recurrence in breast cancer patients treated with doxorubicin-based adjuvant chemotherapy.


METHODS
We prospectively accrued 152 patients with stage I to III breast cancer treated with a doxorubicin-based chemotherapy in an adjuvant setting. Standardized treatment and surveillance protocols were used. eIF4E and TLK1B protein levels were quantified using Western blots, and patients were divided into tertiles based on previously reported stratification of eIF4E and TLK1B levels. Primary end points were cancer recurrence and death. Statistical analysis included Spearman's correlation, Kaplan-Meier survival analysis, log rank test, and the Cox proportional hazard model.


RESULTS
The degree of TLK1B overexpression was highly correlated with the degree of eIF4E elevation (r=0.25, p=0.0025, Spearman rank correlation). Patients whose tumors were in the highest tertile for eIF4E overexpression had a higher risk for cancer recurrence and cancer death (p=0.015 and 0.049, respectively, log rank test). After adjusting for T-stage, nodal status, age, and estrogen receptor and progesterone receptor status, patients with tumors in the highest tertile of TLK1B overexpression treated with doxorubicin were 1.7-fold more likely to suffer recurrence than those in the low TLK1B group treated similarly (p=0.0078, CI, 1.17 to 2.75, Cox model).


CONCLUSIONS
TLK1B overexpression was highly correlated with the level of eIF4E elevation. High TLK1B in cancer specimens was associated with a higher risk for cancer recurrence in patients treated with doxorubicin-based adjuvant chemotherapy.
Byrnes
Kerry W
KW
Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
DeBenedetti
Arrigo
A
Holm
Neal T
NT
Luke
Jay
J
Nunez
Jade
J
Chu
Quyen D
QD
Meschonat
Carol
C
Abreo
Fleurette
F
Johnson
Lester W
LW
Li
Benjamin D L
BD
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D044584:Carcinoma, Ductal / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D004317:Doxorubicin / Q000627:therapeutic use*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018570:Risk Assessment
D000903:Antibiotics, Antineoplastic; D039561:Eukaryotic Initiation Factor-4E; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; C425323:TLK1 protein, human