| First Author | Jain S | Year | 2015 |
| Journal | Cancer Res | Volume | 75 |
| Issue | 22 | Pages | 4863-75 |
| PubMed ID | 26383165 | Mgi Jnum | J:226777 |
| Mgi Id | MGI:5698561 | Doi | 10.1158/0008-5472.CAN-14-2345 |
| Citation | Jain S, et al. (2015) Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer. Cancer Res 75(22):4863-75 |
| abstractText | 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. (c)2015 AACR. |
