PT  - JOURNAL ARTICLE
AU  - Soni, Alpana
AU  - Akcakanat, Argun
AU  - Singh, Gopal
AU  - Luyimbazi, David
AU  - Zheng, Yuhuan
AU  - Kim, Doyil
AU  - Gonzalez-Angulo, Ana
AU  - Meric-Bernstam, Funda
TI  - eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling
AID  - 10.1158/1535-7163.MCT-07-2357
DP  - 2008 Jul 01
TA  - Molecular Cancer Therapeutics
PG  - 1782--1788
VI  - 7
IP  - 7
4099  - http://mct.aacrjournals.org/content/7/7/1782.short
4100  - http://mct.aacrjournals.org/content/7/7/1782.full
SO  - Mol Cancer Ther2008 Jul 01; 7
AB  - Activation of translation initiation is essential for the malignant phenotype and is emerging as a potential therapeutic target. Translation is regulated by the expression of translation initiation factor 4E (eIF4E) as well as the interaction of eIF4E with eIF4E-binding proteins (e.g., 4E-BP1). Rapamycin inhibits translation initiation by decreasing the phosphorylation of 4E-BP1, increasing eIF4E/4E-BP1 interaction. However, rapamycin also inhibits S6K phosphorylation, leading to feedback loop activation of Akt. We hypothesized that targeting eIF4E directly would inhibit breast cancer cell growth without activating Akt. We showed that eIF4E is ubiquitously expressed in breast cancer cell lines. eIF4E knockdown by small interfering RNA inhibited growth in different breast cancer cell subtypes including triple-negative (estrogen receptor/progesterone receptor/HER-2–negative) cancer cells. eIF4E knockdown inhibited the growth of cells with varying total and phosphorylated 4E-BP1 levels and inhibited rapamycin-insensitive as well as rapamycin-sensitive cell lines. eIF4E knockdown led to a decrease in expression of cyclin D1, Bcl-2, and Bcl-xL. eIF4E knockdown did not lead to Akt phosphorylation but did decrease 4E-BP1 expression. We conclude that eIF4E is a promising target for breast cancer therapy. eIF4E-targeted therapy may be efficacious in a variety of breast cancer subtypes including triple-negative tumors for which currently there are no targeted therapies. Unlike rapamycin and its analogues, eIF4E knockdown is not associated with Akt activation. [Mol Cancer Ther 2008;7(7):1782–8]