14-3-3zeta Cooperates with ErbB2 to promote ductal carcinoma in situ progression to invasive breast cancer by inducing epithelial-mesenchymal transition.
ErbB2, a metastasis-promoting oncoprotein, is overexpressed in approximately 25% of invasive/metastatic breast cancers, but in 50%-60% of noninvasive ductal carcinomas in situ (DCIS). It has been puzzling how a subset of ErbB2-overexpressing DCIS develops into invasive breast cancer (IBC). We found that co-overexpression of 14-3-3zeta in ErbB2-overexpressing DCIS conferred a higher risk of progression to IBC. ErbB2 and 14-3-3zeta overexpression, respectively, increased cell migration and decreased cell adhesion, two prerequisites of tumor cell invasion. 14-3-3zeta overexpression reduced cell adhesion by activating the TGF-beta/Smads pathway that led to ZFHX1B/SIP-1 upregulation, E-cadherin loss, and epithelial-mesenchymal transition. Importantly, patients whose breast tumors overexpressed both ErbB2 and 14-3-3zeta had higher rates of metastatic recurrence and death than those whose tumors overexpressed only one.
Lu
Jing
J
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Guo
Hua
H
Treekitkarnmongkol
Warapen
W
Li
Ping
P
Zhang
Jian
J
Shi
Bin
B
Ling
Chen
C
Zhou
Xiaoyan
X
Chen
Tongzhen
T
Chiao
Paul J
PJ
Feng
Xinhua
X
Seewaldt
Victoria L
VL
Muller
William J
WJ
Sahin
Aysegul
A
Hung
Mien-Chie
MC
Yu
Dihua
D
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018734:Genes, erbB-2; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012307:Risk Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
D048948:14-3-3 Proteins; D015820:Cadherins; C108381:GEMIN2 protein, human; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1