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Article: Src inhibition blocks c-Myc translation and glucose metabolism to prevent the development of breast cancer

TitleSrc inhibition blocks c-Myc translation and glucose metabolism to prevent the development of breast cancer
Authors
Issue Date2015
Citation
Cancer Research, 2015, v. 75, n. 22, p. 4863-4875 How to Cite?
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 threedimensional 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.
Persistent Identifierhttp://hdl.handle.net/10722/342232
ISSN
2023 Impact Factor: 12.5
2023 SCImago Journal Rankings: 3.468
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorJain, Shalini-
dc.contributor.authorWang, Xiao-
dc.contributor.authorChang, Chia Chi-
dc.contributor.authorIbarra-Drendall, Catherine-
dc.contributor.authorWang, Hai-
dc.contributor.authorZhang, Qingling-
dc.contributor.authorBrady, Samuel W.-
dc.contributor.authorLi, Ping-
dc.contributor.authorZhao, Hong-
dc.contributor.authorDobbs, Jessica-
dc.contributor.authorKyrish, Matt-
dc.contributor.authorTkaczyk, Tomasz S.-
dc.contributor.authorAmbrose, Adrian-
dc.contributor.authorSistrunk, Christopher-
dc.contributor.authorArun, Banu K.-
dc.contributor.authorRichards-Kortum, Rebecca-
dc.contributor.authorJia, Wei-
dc.contributor.authorSeewaldt, Victoria L.-
dc.contributor.authorYu, Dihua-
dc.date.accessioned2024-04-17T07:02:13Z-
dc.date.available2024-04-17T07:02:13Z-
dc.date.issued2015-
dc.identifier.citationCancer Research, 2015, v. 75, n. 22, p. 4863-4875-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/342232-
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 threedimensional 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.-
dc.languageeng-
dc.relation.ispartofCancer Research-
dc.titleSrc inhibition blocks c-Myc translation and glucose metabolism to prevent the development of breast cancer-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/0008-5472.CAN-14-2345-
dc.identifier.pmid26383165-
dc.identifier.scopuseid_2-s2.0-84955114584-
dc.identifier.volume75-
dc.identifier.issue22-
dc.identifier.spage4863-
dc.identifier.epage4875-
dc.identifier.eissn1538-7445-
dc.identifier.isiWOS:000365602600019-

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