In vivo study of breast carcinoma radiosensitization by targeting eIF4E.
BACKGROUND
Eukaryotic initiation factor eIF4E, an important regulator of translation, plays a crucial role in the malignant transformation, progression and radioresistance of many human solid tumors. The overexpression of this gene has been associated with tumor formation in a wide range of human malignancies, including breast cancer. In the present study, we attempted to explore the use of eIF4E as a therapeutic target to enhance radiosensitivity for breast carcinomas in a xenograft BALB/C mice model.


METHODS
Ninety female BALB/C mice transfected with EMT-6 cells were randomly divided into six groups: control, irradiation (IR), pSecX-t4EBP1, pSecX-t4EBP1+irradiation, pSecX and pSecX+irradiation. At the end of the experiments, all mice were sacrificed, the xenografts were harvested to measure the tumor volume and mass, and the tumor inhibition rates were calculated. Apoptosis was detected with a flow cytometric assay. Immunohistochemistry was used to detect the expression of HIF-1α.


RESULTS
The xenografts in pSecX-t4EBP1 mice showed a significantly delayed growth and smaller tumor volume, with a higher tumor inhibition rate compared with the control and pSecX groups. A similar result was obtained in the pSecX-t4EBP1+IR group compared with IR alone and pSecX+irradiation. The expression of HIF-1α in the tumor cells was significantly decreased, while the apoptosis index was much higher.


CONCLUSIONS
pSecX-t4EBP1 can significantly inhibit tumor growth and enhance the radiosensitivity of breast carcinoma xenografts in BALB/C mice. This is possibly associated with the downregulation of HIF-1α expression, which suggests that pSecX-t4EBP1 may serve as an ideal molecular target for the radiosensitization of breast carcinoma.
Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032, China.
Hua
H
Yang
Li-Wen
LW
Li
Mei
M
Shi
Jian-Hua
JH
Wang
Feng
F
Xiao
Bin
B
Zhou
Li-Qiong
LQ
Diao
Xiao-Li
XL
Long
Xiao-Li
XL
Liu
Lin
L
Xu
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015536:Down-Regulation; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000235:genetics; D011836:Radiation Tolerance; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins