American Association for Cancer Research
00085472can142345-sup-135846_4_supp_3055338_nrg00s.png (685.31 kB)

Supplementary Figure S2 from Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer

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posted on 2023-03-31, 00:09 authored by Shalini Jain, Xiao Wang, Chia-Chi Chang, Catherine Ibarra-Drendall, Hai Wang, Qingling Zhang, Samuel W. Brady, Ping Li, Hong Zhao, Jessica Dobbs, Matt Kyrish, Tomasz S. Tkaczyk, Adrian Ambrose, Christopher Sistrunk, Banu K. Arun, Rebecca Richards-Kortum, Wei Jia, Victoria L. Seewaldt, Dihua Yu

Saracatinib increases tumor free and overall survival in ER- mammary mouse models.



Preventing 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. Cancer Res; 75(22); 4863–75. ©2015 AACR.