title: Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology Program, University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ibarra-Drendall
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology Program, University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Brady
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Bioengineering Department, Rice University, Houston, Texas.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dobbs
authors.affiliation: Bioengineering Department, Rice University, Houston, Texas.
authors.forename: Matt
authors.initials: M
authors.lastname: Kyrish
authors.affiliation: Bioengineering Department, Rice University, Houston, Texas.
authors.forename: Tomasz S
authors.initials: TS
authors.lastname: Tkaczyk
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ambrose
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sistrunk
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Banu K
authors.initials: BK
authors.lastname: Arun
authors.affiliation: Bioengineering Department, Rice University, Houston, Texas.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Richards-Kortum
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii at Monoa, Honolulu. Hawaii.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Seewaldt
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for Molecular Medicine, China Medical University, Taichung, Taiwan. dyu@mdanderson.org.
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D016259:Genes, myc / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D011799:Quinazolines; D011960:Receptors, Estrogen; C515233:saracatinib; D019061:src-Family Kinases; D005947:Glucose