PMID- 18332865
OWN - NLM
STAT- MEDLINE
DCOM- 20080807
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 27
IP  - 29
DP  - 2008 Jul 3
TI  - Suppression of PTEN function increases breast cancer chemotherapeutic drug 
      resistance while conferring sensitivity to mTOR inhibitors.
PG  - 4086-95
LID - 10.1038/onc.2008.49 [doi]
AB  - Ectopic expression of mutant forms of phosphatase and tensin homologue deleted on 
      chromosome 10 (PTEN) lacking lipid (G129E) or lipid and protein (C124S) 
      phosphatase activity decreased sensitivity of MCF-7 breast cancer cells, which 
      have wild-type PTEN, to doxorubicin and increased sensitivity to the mammalian 
      target of rapamycin (mTOR) inhibitor rapamycin. Cells transfected with a mutant 
      PTEN gene lacking both lipid and protein phosphatase activities were more 
      resistant to doxorubicin than cells transfected with the PTEN mutant lacking 
      lipid phosphatase activity indicating that the protein phosphatase activity of 
      PTEN was also important in controlling the sensitivity to doxorubicin, while no 
      difference was observed between the lipid (G129E) and lipid and protein (C124S) 
      phosphatase PTEN mutants in terms of sensitivity to rapamycin. A synergistic 
      inhibitory interaction was observed when doxorubicin was combined with rapamycin 
      in the phosphatase-deficient PTEN-transfected cells. Interference with the lipid 
      phosphatase activity of PTEN was sufficient to activate Akt/mTOR/p70S6K 
      signaling. These studies indicate that disruption of the normal activity of the 
      PTEN phosphatase can have dramatic effects on the therapeutic sensitivity of 
      breast cancer cells. Mutations in the key residues which control PTEN lipid and 
      protein phosphatase may act as dominant-negative mutants to suppress endogenous 
      PTEN and alter the sensitivity of breast cancer patients to chemo- and targeted 
      therapies.
FAU - Steelman, L S
AU  - Steelman LS
AD  - Department of Microbiology and Immunology, Brody School of Medicine, East 
      Carolina University, Greenville, NC 27858, USA.
FAU - Navolanic, P M
AU  - Navolanic PM
FAU - Sokolosky, M L
AU  - Sokolosky ML
FAU - Taylor, J R
AU  - Taylor JR
FAU - Lehmann, B D
AU  - Lehmann BD
FAU - Chappell, W H
AU  - Chappell WH
FAU - Abrams, S L
AU  - Abrams SL
FAU - Wong, E W T
AU  - Wong EW
FAU - Stadelman, K M
AU  - Stadelman KM
FAU - Terrian, D M
AU  - Terrian DM
FAU - Leslie, N R
AU  - Leslie NR
FAU - Martelli, A M
AU  - Martelli AM
FAU - Stivala, F
AU  - Stivala F
FAU - Libra, M
AU  - Libra M
FAU - Franklin, R A
AU  - Franklin RA
FAU - McCubrey, J A
AU  - McCubrey JA
LA  - eng
GR  - G9403619/MRC_/Medical Research Council/United Kingdom
GR  - R01 CA098195/CA/NCI NIH HHS/United States
GR  - R01CA098195/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080310
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
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 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Amino Acid Substitution
MH  - Antibiotics, Antineoplastic/agonists/pharmacology/therapeutic use
MH  - Breast Neoplasms/drug therapy/*enzymology/genetics
MH  - Cell Line, Tumor
MH  - Doxorubicin/agonists/pharmacology/therapeutic use
MH  - *Drug Resistance, Neoplasm/drug effects/genetics
MH  - Drug Synergism
MH  - Female
MH  - Gene Expression
MH  - Humans
MH  - *Mutation, Missense
MH  - PTEN Phosphohydrolase/antagonists & inhibitors/genetics/*metabolism
MH  - Protein Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism
MH  - *Signal Transduction/drug effects/genetics
MH  - Sirolimus/agonists/pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
PMC - PMC3836277
MID - NIHMS527893
EDAT- 2008/03/12 09:00
MHDA- 2008/08/08 09:00
PMCR- 2013/11/21
CRDT- 2008/03/12 09:00
PHST- 2008/03/12 09:00 [pubmed]
PHST- 2008/08/08 09:00 [medline]
PHST- 2008/03/12 09:00 [entrez]
PHST- 2013/11/21 00:00 [pmc-release]
AID - onc200849 [pii]
AID - 10.1038/onc.2008.49 [doi]
PST - ppublish
SO  - Oncogene. 2008 Jul 3;27(29):4086-95. doi: 10.1038/onc.2008.49. Epub 2008 Mar 10.