Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity

Linda A. DeGraffenried, William E. Friedrichs, Douglas H. Russell, Elissa J. Donzis, Amanda K. Middleton, Jessica M. Silva, Richard A. Roth, Manuel Hidalgo

Research output: Contribution to journalArticle

Abstract

The Akt kinase is a serine/threonine protein kinase that has been implicated in mediating a variety of biological responses. Studies show that high Akt activity in breast carcinoma is associated with a poor pathophenotype, as well as hormone and chemotherapy resistance. Additionally, high Akt activity is associated with other features of poor prognosis. Thus, a chemotherapeutic agent directed specifically toward tumors with high Akt activity could prove extremely potent in treating those breast tumors with the most aggressive phenotypes. Several studies have demonstrated that rapamycin, which inhibits mammalian target of rapamycin (mTOR), a downstream target of Akt, sensitizes certain resistant cancer cells to chemotherapeutic agents. This study evaluated the efficacy of mTOR inhibition in the treatment of tamoxifen-resistant breast carcinoma characterized by high Akt activity. We found that MCF-7 breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions and are resistant to the growth inhibitory effects of tamoxifen, both in vitro as well as in vivo in xenograft models. Cotreatment with the mTOR inhibitor rapamycin in vitro, or the ester of rapamycin, CCI-779 (Wyeth) in vivo, inhibited mTOR activity and restored sensitivity to tamoxifen, suggesting that Akt-induced tamoxifen resistance is mediated in part by signaling through the mTOR pathway. Although the mechanism underlying the synergism remains to be understood, the results were associated with rapamycin's ability to block transcriptional activity mediated by estrogen receptor α, as assessed by reporter gene assays with estrogen-responsive element luciferase. These data corroborate prior findings indicating that Akt activation induces resistance to tamoxifen in breast cancer cells. Importantly, these data indicate a novel mechanism for tamoxifen resistance and suggest that blockage of the phosphatidylinositol 3′-kinase/Akt signaling pathway by mTOR inhibition effectively restores the susceptibility of these cells to tamoxifen. These data may have implication for future clinical studies of mTOR inhibition in breast carcinoma.

Original languageEnglish (US)
Pages (from-to)8059-8067
Number of pages9
JournalClinical Cancer Research
Volume10
Issue number23
DOIs
StatePublished - Dec 1 2004

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Sirolimus
Tamoxifen
Breast Neoplasms
Estrogens
Phosphatidylinositol 3-Kinase
Protein-Serine-Threonine Kinases
Luciferases
Reporter Genes
Heterografts
Estrogen Receptors
Neoplasms
Esters
Phosphotransferases
Hormones
Phenotype
Drug Therapy
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

DeGraffenried, L. A., Friedrichs, W. E., Russell, D. H., Donzis, E. J., Middleton, A. K., Silva, J. M., ... Hidalgo, M. (2004). Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clinical Cancer Research, 10(23), 8059-8067. https://doi.org/10.1158/1078-0432.CCR-04-0035

Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. / DeGraffenried, Linda A.; Friedrichs, William E.; Russell, Douglas H.; Donzis, Elissa J.; Middleton, Amanda K.; Silva, Jessica M.; Roth, Richard A.; Hidalgo, Manuel.

In: Clinical Cancer Research, Vol. 10, No. 23, 01.12.2004, p. 8059-8067.

Research output: Contribution to journalArticle

DeGraffenried, LA, Friedrichs, WE, Russell, DH, Donzis, EJ, Middleton, AK, Silva, JM, Roth, RA & Hidalgo, M 2004, 'Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity', Clinical Cancer Research, vol. 10, no. 23, pp. 8059-8067. https://doi.org/10.1158/1078-0432.CCR-04-0035
DeGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clinical Cancer Research. 2004 Dec 1;10(23):8059-8067. https://doi.org/10.1158/1078-0432.CCR-04-0035
DeGraffenried, Linda A. ; Friedrichs, William E. ; Russell, Douglas H. ; Donzis, Elissa J. ; Middleton, Amanda K. ; Silva, Jessica M. ; Roth, Richard A. ; Hidalgo, Manuel. / Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 23. pp. 8059-8067.
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