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Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
19:44

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

Published on: May 30, 2012

Akt-induced tamoxifen resistance is associated with altered FKHR regulation

Jessica Silva1, David A Cavazos, Elissa Donzis

  • 1The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

Cancer Investigation
|October 24, 2007
PubMed

Insights

High Akt kinase activity promotes breast cancer cell survival and tamoxifen resistance by inhibiting apoptosis. Inhibiting Akt restores sensitivity to tamoxifen, suggesting Akt pathway modulation for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Akt kinase is implicated in various biological responses and is linked to poor prognosis in breast cancer.
  • Akt signaling contributes to resistance against hormone therapy, including tamoxifen.
  • Akt promotes cell survival by inhibiting apoptosis and enhancing survival gene transcription.

Purpose of the Study:

  • To investigate the role of specific Akt pathway components in cellular response to tamoxifen.
  • To determine if constitutive Akt activation confers tamoxifen resistance in breast cancer cells.

Main Methods:

  • Transfection of MCF-7 cells with a constitutively active Akt expression plasmid.
  • In vitro and in vivo (xenograft models) assessment of cell proliferation and tamoxifen response.
  • Analysis of apoptotic markers, including FKHR transcription factor activation and TUNEL assay.

Main Results:

  • MCF-7 cells expressing constitutively active Akt showed proliferation under low estrogen and resistance to tamoxifen.
  • Tamoxifen treatment did not alter FKHR expression in Akt-expressing xenografts, unlike controls.
  • Akt-expressing xenografts exhibited lower apoptosis levels compared to control xenografts after tamoxifen treatment.
  • Inhibition of Akt activity in vitro restored tamoxifen-induced apoptosis in Akt-expressing cells.

Conclusions:

  • Constitutive Akt activation confers resistance to tamoxifen in breast cancer.
  • Altered apoptotic responses mediated by Akt are a key mechanism of tamoxifen resistance.
  • Targeting the Akt pathway may overcome tamoxifen resistance in breast cancer.

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