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2015 ; 75
(22
): 4863-75
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Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the
Development of Breast Cancer
#MMPMID26383165
Jain S
; Wang X
; Chang CC
; Ibarra-Drendall C
; Wang H
; Zhang Q
; Brady SW
; Li P
; Zhao H
; Dobbs J
; Kyrish M
; Tkaczyk TS
; Ambrose A
; Sistrunk C
; Arun BK
; Richards-Kortum R
; Jia W
; Seewaldt VL
; Yu D
Cancer Res
2015[Nov]; 75
(22
): 4863-75
PMID26383165
show ga
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.