Akt-induced tamoxifen resistance is associated with altered FKHR regulation

Jessica Silva, David A. Cavazos, Elissa Donzis, William E. Friedrichs, Robert A Marciniak, Linda A. DeGraffenried

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The Akt kinase is a serine/threonine protein kinase that has been implicated in mediating a variety of biological responses, is associated with a poor pathophenotype in breast carcinoma, and is involved in hormone and chemotherapy resistance, including resistance to the antiestrogen, tamoxifen. Akt promotes cell survival by phosphorylating and inactivating proapoptotic proteins and increasing the transcription of survival genes. To explore the role that specific components of the Akt kinase pathway play in the cellular response to tamoxifen, we transfected MCF-7 cells with an expression plasmid for a constitutively active Akt. 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. Initial analysis of the molecular responses in the Akt/MCF-7 xenografts to tamoxifen suggests that high Akt activity alters apoptotic responses to tamoxifen. Control MCF-7 xenografts demonstrated activation of the proapoptotic forkhead (FKHR) transcription factor in response to tamoxifen treatment, while the xenografts expressing the constitutively active Akt transgene demonstrated no alterations in FKHR expression. In addition, TUNEL analysis demonstrated higher levels of apoptosis in the control xenografts in response to tamoxifen treatment compared to the Akt xenografts. Inhibition of Akt activity in vitro restored apoptotic responses to tamoxifen in the Akt/MCF-7 cells to those observed in the control cells. These data suggest that alteration of survival responses is an important mechanism by which Akt confers resistance to tamoxifen.

Original languageEnglish (US)
Pages (from-to)569-573
Number of pages5
JournalCancer Investigation
Volume25
Issue number7
DOIs
StatePublished - Oct 2007

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Tamoxifen
Heterografts
MCF-7 Cells
Phosphotransferases
Breast Neoplasms
Forkhead Transcription Factors
Estrogen Receptor Modulators
Protein-Serine-Threonine Kinases
In Situ Nick-End Labeling
Transgenes
Cell Survival
Estrogens
Plasmids
Hormones
Apoptosis
Drug Therapy
Cell Line
Therapeutics
Growth

Keywords

  • Akt
  • Breast cancer
  • Forkhead
  • Resistance
  • Tamoxifen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Silva, J., Cavazos, D. A., Donzis, E., Friedrichs, W. E., Marciniak, R. A., & DeGraffenried, L. A. (2007). Akt-induced tamoxifen resistance is associated with altered FKHR regulation. Cancer Investigation, 25(7), 569-573. https://doi.org/10.1080/07357900701513538

Akt-induced tamoxifen resistance is associated with altered FKHR regulation. / Silva, Jessica; Cavazos, David A.; Donzis, Elissa; Friedrichs, William E.; Marciniak, Robert A; DeGraffenried, Linda A.

In: Cancer Investigation, Vol. 25, No. 7, 10.2007, p. 569-573.

Research output: Contribution to journalArticle

Silva, J, Cavazos, DA, Donzis, E, Friedrichs, WE, Marciniak, RA & DeGraffenried, LA 2007, 'Akt-induced tamoxifen resistance is associated with altered FKHR regulation', Cancer Investigation, vol. 25, no. 7, pp. 569-573. https://doi.org/10.1080/07357900701513538
Silva, Jessica ; Cavazos, David A. ; Donzis, Elissa ; Friedrichs, William E. ; Marciniak, Robert A ; DeGraffenried, Linda A. / Akt-induced tamoxifen resistance is associated with altered FKHR regulation. In: Cancer Investigation. 2007 ; Vol. 25, No. 7. pp. 569-573.
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