PMID- 15501954
OWN - NLM
STAT- MEDLINE
DCOM- 20050329
LR  - 20220330
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 10
IP  - 20
DP  - 2004 Oct 15
TI  - Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 
      overexpression predicts tumor progression in breast cancers.
PG  - 6779-88
AB  - The Akt/mammalian target of rapamycin (mTOR)/4E-BP1 pathway is considered to be a 
      central regulator of protein synthesis, involving the regulation of cell 
      proliferation, differentiation, and survival. The inhibitors of mTOR as 
      anticancer reagents are undergoing active evaluation in various malignancies 
      including breast cancer. However, the activation status of the Akt/mTOR/4E-BP1 
      pathway and its potential roles in breast cancers remain unknown. Thus, we 
      examined 165 invasive breast cancers with specific antibodies for the 
      phosphorylation of Akt, mTOR, and 4E-BP1 by immunohistochemistry and compared 
      them with normal breast epithelium, fibroadenoma, intraductal hyperplasia, and 
      ductal carcinoma in situ. We discovered that the phosphorylation of Akt, mTOR, 
      and 4E-BP1 increased progressively from normal breast epithelium to hyperplasia 
      and abnormal hyperplasia to tumor invasion. Phosphorylated Akt, mTOR, and 4E-BP1 
      were positively associated with ErbB2 overexpression. Survival analysis showed 
      that phosphorylation of each of these three markers was associated with poor 
      disease-free survival independently. In vitro, we further confirmed the causal 
      relationship between ErbB2 overexpression and mTOR activation, which was 
      associated with enhanced invasive ability and sensitivity to a mTOR inhibitor, 
      rapamycin. Our results, for the first time, demonstrate the following: (a) high 
      levels of phosphorylation of Akt, mTOR, and 4E-BP1 in breast cancers, indicating 
      activation of the Akt/mTOR/4E-BP1 pathway in breast cancer development and 
      progression; (b) a link between ErbB2 and the Akt/mTOR/4E-BP1 pathway in breast 
      cancers in vitro and in vivo, indicating the possible role of Akt/mTOR activation 
      in ErbB2-mediated breast cancer progression; and (c) a potential role for this 
      pathway in predicting the prognosis of patients with breast cancer, especially 
      those treated with mTOR inhibitors.
FAU - Zhou, Xiaoyan
AU  - Zhou X
AD  - Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer 
      Center, Houston, Texas 77030, USA.
FAU - Tan, Ming
AU  - Tan M
FAU - Stone Hawthorne, Valerie
AU  - Stone Hawthorne V
FAU - Klos, Kristine S
AU  - Klos KS
FAU - Lan, Keng-Hsueh
AU  - Lan KH
FAU - Yang, Ying
AU  - Yang Y
FAU - Yang, Wentao
AU  - Yang W
FAU - Smith, Terry L
AU  - Smith TL
FAU - Shi, Daren
AU  - Shi D
FAU - Yu, Dihua
AU  - Yu D
LA  - eng
GR  - 2R01-CA60488/CA/NCI NIH HHS/United States
GR  - 5PO1-CA099031/CA/NCI NIH HHS/United States
GR  - P30-CA16672/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Adult
MH  - Aged
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Biomarkers, Tumor/*analysis
MH  - Breast Neoplasms/*genetics/*pathology
MH  - Carcinoma, Intraductal, Noninfiltrating/*genetics/*pathology
MH  - Carrier Proteins/*biosynthesis/metabolism/pharmacology
MH  - Cell Cycle Proteins
MH  - Cell Proliferation
MH  - Disease Progression
MH  - Female
MH  - *Gene Expression Profiling
MH  - Genes, erbB-2
MH  - Humans
MH  - Hyperplasia
MH  - Immunohistochemistry
MH  - Middle Aged
MH  - Neoplasm Invasiveness
MH  - Phosphoproteins/*biosynthesis/metabolism/pharmacology
MH  - Phosphorylation
MH  - Protein Kinases/*biosynthesis/metabolism/pharmacology
MH  - Protein Serine-Threonine Kinases
MH  - Protein-Tyrosine Kinases/*biosynthesis/metabolism/pharmacology
MH  - Proto-Oncogene Proteins
MH  - Proto-Oncogene Proteins c-akt
MH  - Sirolimus/pharmacology
MH  - Survival Analysis
MH  - TOR Serine-Threonine Kinases
EDAT- 2004/10/27 09:00
MHDA- 2005/03/30 09:00
CRDT- 2004/10/27 09:00
PHST- 2004/10/27 09:00 [pubmed]
PHST- 2005/03/30 09:00 [medline]
PHST- 2004/10/27 09:00 [entrez]
AID - 10/20/6779 [pii]
AID - 10.1158/1078-0432.CCR-04-0112 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2004 Oct 15;10(20):6779-88. doi: 10.1158/1078-0432.CCR-04-0112.