PMID- 14871980
OWN - NLM
STAT- MEDLINE
DCOM- 20040928
LR  - 20211203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 10
IP  - 3
DP  - 2004 Feb 1
TI  - Determinants of rapamycin sensitivity in breast cancer cells.
PG  - 1013-23
AB  - PURPOSE: Rapamycin inhibits the serine-threonine kinase mammalian target of 
      rapamycin (mTOR), blocking phosphorylation of p70 S6 kinase (S6K1) and 4E-binding 
      protein 1 (4E-BP1) and inhibiting protein translation and cell cycle progression. 
      Rapamycin and its analogues are currently being tested in clinical trials as 
      novel-targeted anticancer agents. Although rapamycin analogues show activity in 
      clinical trials, only some of the treated patients respond. The purpose of this 
      study is to identify determinants of rapamycin sensitivity that may assist the 
      selection of appropriate patients for therapy. EXPERIMENTAL DESIGN: Breast cancer 
      cell lines representing a spectrum of aberrations in the mTOR signaling pathway 
      were tested for rapamycin sensitivity. The expression and phosphorylation state 
      of multiple components of the pathway were tested by Western blot analysis, in 
      the presence and absence of rapamycin. RESULTS: Cell proliferation was 
      significantly inhibited in response to rapamycin in 12 of 15 breast cancer cell 
      lines. The ratio of total protein levels of 4E-BP1 to its binding partner 
      eukaryotic initiation factor 4E did not predict rapamycin sensitivity. In 
      contrast, overexpression of S6K1, and phosphorylated Akt independent of 
      phosphatase and tensin homologue deleted from chromosome 10 status, were 
      associated with rapamycin sensitivity. Targeting S6K1 and Akt with small 
      interfering RNA and dominant-negative constructs, respectively, decreased 
      rapamycin sensitivity. Rapamycin inhibited the phosphorylation of S6K1, ribosomal 
      S6 protein, and 4E-BP1 in rapamycin-resistant as well as -sensitive cells, 
      indicating that its ability to inhibit the mTOR pathway is not sufficient to 
      confer sensitivity to rapamycin. In contrast, rapamycin treatment was associated 
      with decreased cyclin D1 levels in the rapamycin-sensitive cells but not in 
      rapamycin-resistant cells. CONCLUSIONS: Overexpression of S6K1 and expression of 
      phosphorylated Akt should be evaluated as predictors of rapamycin sensitivity in 
      breast cancer patients. Furthermore, changes in cyclin D1 levels provide a 
      potential pharmacodynamic marker of response to rapamycin.
FAU - Noh, Woo-Chul
AU  - Noh WC
AD  - Korea Cancer Center Hospital, Nowon-gu, Seoul, Korea.
FAU - Mondesire, Wallace H
AU  - Mondesire WH
FAU - Peng, Junying
AU  - Peng J
FAU - Jian, Weiguo
AU  - Jian W
FAU - Zhang, Haixia
AU  - Zhang H
FAU - Dong, JinJiang
AU  - Dong J
FAU - Mills, Gordon B
AU  - Mills GB
FAU - Hung, Mien-Chie
AU  - Hung MC
FAU - Meric-Bernstam, Funda
AU  - Meric-Bernstam F
LA  - eng
GR  - 1K08 CA 91895-01/CA/NCI NIH HHS/United States
GR  - 5T32 CA 09599/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
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 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 136601-57-5 (Cyclin D1)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
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 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Blotting, Western
MH  - Breast Neoplasms/*drug therapy
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle
MH  - Cell Cycle Proteins
MH  - Cell Division
MH  - Cell Line, Tumor
MH  - Cyclin D1/biosynthesis/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Genes, Dominant
MH  - Humans
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA, Small Interfering/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
EDAT- 2004/02/12 05:00
MHDA- 2004/09/29 05:00
CRDT- 2004/02/12 05:00
PHST- 2004/02/12 05:00 [pubmed]
PHST- 2004/09/29 05:00 [medline]
PHST- 2004/02/12 05:00 [entrez]
AID - 10.1158/1078-0432.ccr-03-0043 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2004 Feb 1;10(3):1013-23. doi: 10.1158/1078-0432.ccr-03-0043.