Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors

L S Steelman, P M Navolanic, M L Sokolosky, J R Taylor, B D Lehmann, W H Chappell, S L Abrams, E W T Wong, K M Stadelman, D M Terrian, Nick Leslie, A M Martelli, F Stivala, M Libra, R A Franklin, J A McCubrey

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)4086-4095
Number of pages10
JournalOncogene
Volume27
Issue number29
DOIs
Publication statusPublished - 3 Jul 2008

Keywords

  • Amino Acid Substitution
  • Antibiotics, Antineoplastic
  • Breast Neoplasms
  • Cell Line, Tumor
  • Doxorubicin
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Gene Expression
  • Humans
  • Mutation, Missense
  • PTEN Phosphohydrolase
  • Protein Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Signal Transduction
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • Transfection

Fingerprint Dive into the research topics of 'Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors'. Together they form a unique fingerprint.

  • Cite this

    Steelman, L. S., Navolanic, P. M., Sokolosky, M. L., Taylor, J. R., Lehmann, B. D., Chappell, W. H., Abrams, S. L., Wong, E. W. T., Stadelman, K. M., Terrian, D. M., Leslie, N., Martelli, A. M., Stivala, F., Libra, M., Franklin, R. A., & McCubrey, J. A. (2008). Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors. Oncogene, 27(29), 4086-4095. https://doi.org/10.1038/onc.2008.49