Jain, ShaliniWang, XiaoChang, Chia-ChiIbarra-Drendall, CatherineWang, HaiZhang, QinglingBrady, Samuel W.Li, PingZhao, HongDobbs, JessicaKyrish, MattTkaczyk, Tomasz S.Ambrose, AdrianSistrunk, ChristopherArun, Banu K.Richards-Kortum, RebeccaJia, WeiSeewaldt, Victoria L.Yu, Dihua2017-05-122017-05-122015Jain, Shalini, Wang, Xiao, Chang, Chia-Chi, et al.. "Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer." <i>Cancer Research,</i> 75, no. 22 (2015) AACR: 4863-4875. http://dx.doi.org/10.1158/0008-5472.CAN-14-2345.https://hdl.handle.net/1911/94244Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor–positive (ER+) breast cancer development, but estrogen receptor–negative (ER−) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small-molecule inhibitor saracatinib prevented the disorganized three-dimensional growth of ER− mammary epithelial cells in vitro and delayed the development of premalignant lesions and tumors in vivo in mouse models developing HER2+ and ER− mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2–MNK1–eIF4E–mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers.engThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by AACR.Journal articlehttp://dx.doi.org/10.1158/0008-5472.CAN-14-2345