PMID- 16489002
OWN - NLM
STAT- MEDLINE
DCOM- 20060413
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 4
DP  - 2006 Feb 15
TI  - ErbB2 increases vascular endothelial growth factor protein synthesis via 
      activation of mammalian target of rapamycin/p70S6K leading to increased 
      angiogenesis and spontaneous metastasis of human breast cancer cells.
PG  - 2028-37
AB  - ErbB2 overexpression in breast tumors results in increased metastasis and 
      angiogenesis and reduced survival. To study ErbB2 signaling mechanisms in 
      metastasis and angiogenesis, we did a spontaneous metastasis assay using 
      MDA-MB-435 human breast cancer cells stably transfected with constitutively 
      active ErbB2 kinase (V659E), a kinase-dead mutant of ErbB2 (K753M), or vector 
      control (neo). Mice injected with V659E had increased metastasis incidence and 
      tumor microvessel density than mice injected with K753M or control. Increased 
      angiogenesis in vivo from the V659E transfectants paralleled increased angiogenic 
      potential in vitro. V659E produced increased vascular endothelial growth factor 
      (VEGF) through increased VEGF protein synthesis. This was mediated through 
      signaling events involving extracellular signal-regulated kinase, 
      phosphatidylinositol 3-kinase/Akt, mammalian target of rapamycin (mTOR), and 
      p70S6K. The V659E xenografts also had significantly increased phosphorylated Akt, 
      phosphorylated p70S6K, and VEGF compared with controls. To validate the clinical 
      relevance of these findings, we examined 155 human breast tumor samples. Human 
      tumors that overexpressed ErbB2, which have been previously shown to have higher 
      VEGF expression, showed significantly higher p70S6K phosphorylation as well. 
      Increased VEGF expression also significantly correlated with higher levels of Akt 
      and mTOR phosphorylation. Additionally, patients with tumors having increased 
      p70S6K phosphorylation showed a trend for worse disease-free survival and 
      increased metastasis. Our findings show that ErbB2 increases VEGF protein 
      production by activating p70S6K in cell lines, xenografts, and in human cancers 
      and suggest that these signaling molecules may serve as targets for 
      antiangiogenic and antimetastatic therapies.
FAU - Klos, Kristine S
AU  - Klos KS
AD  - Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas 77030, USA.
FAU - Wyszomierski, Shannon L
AU  - Wyszomierski SL
FAU - Sun, Menghong
AU  - Sun M
FAU - Tan, Ming
AU  - Tan M
FAU - Zhou, Xiaoyan
AU  - Zhou X
FAU - Li, Ping
AU  - Li P
FAU - Yang, Wentao
AU  - Yang W
FAU - Yin, Guosheng
AU  - Yin G
FAU - Hittelman, Walter N
AU  - Hittelman WN
FAU - Yu, Dihua
AU  - Yu D
LA  - eng
GR  - 1R01-CA109570/CA/NCI NIH HHS/United States
GR  - 2R01-CA60448/CA/NCI NIH HHS/United States
GR  - P01-CA099031/CA/NCI NIH HHS/United States
GR  - P30-CA 16672/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*blood supply/enzymology/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, SCID
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - NIH 3T3 Cells
MH  - Neoplasm Metastasis
MH  - Neovascularization, Pathologic/metabolism/pathology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptor, ErbB-2/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transplantation, Heterologous
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/*biosynthesis
EDAT- 2006/02/21 09:00
MHDA- 2006/04/14 09:00
CRDT- 2006/02/21 09:00
PHST- 2006/02/21 09:00 [pubmed]
PHST- 2006/04/14 09:00 [medline]
PHST- 2006/02/21 09:00 [entrez]
AID - 66/4/2028 [pii]
AID - 10.1158/0008-5472.CAN-04-4559 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Feb 15;66(4):2028-37. doi: 10.1158/0008-5472.CAN-04-4559.