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

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dc.citation.firstpage4863en_US
dc.citation.issueNumber22en_US
dc.citation.journalTitleCancer Researchen_US
dc.citation.lastpage4875en_US
dc.citation.volumeNumber75en_US
dc.contributor.authorJain, Shalinien_US
dc.contributor.authorWang, Xiaoen_US
dc.contributor.authorChang, Chia-Chien_US
dc.contributor.authorIbarra-Drendall, Catherineen_US
dc.contributor.authorWang, Haien_US
dc.contributor.authorZhang, Qinglingen_US
dc.contributor.authorBrady, Samuel W.en_US
dc.contributor.authorLi, Pingen_US
dc.contributor.authorZhao, Hongen_US
dc.contributor.authorDobbs, Jessicaen_US
dc.contributor.authorKyrish, Matten_US
dc.contributor.authorTkaczyk, Tomasz S.en_US
dc.contributor.authorAmbrose, Adrianen_US
dc.contributor.authorSistrunk, Christopheren_US
dc.contributor.authorArun, Banu K.en_US
dc.contributor.authorRichards-Kortum, Rebeccaen_US
dc.contributor.authorJia, Weien_US
dc.contributor.authorSeewaldt, Victoria L.en_US
dc.contributor.authorYu, Dihuaen_US
dc.contributor.orgBioengineeringen_US
dc.date.accessioned2017-05-12T17:10:13Zen_US
dc.date.available2017-05-12T17:10:13Zen_US
dc.date.issued2015en_US
dc.description.abstractPreventing 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.en_US
dc.identifier.citationJain, 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.en_US
dc.identifier.doihttp://dx.doi.org/10.1158/0008-5472.CAN-14-2345en_US
dc.identifier.urihttps://hdl.handle.net/1911/94244en_US
dc.language.isoengen_US
dc.publisherAACRen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by AACR.en_US
dc.titleSrc Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Canceren_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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