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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

19.3K

Protein Kinase A-induced tamoxifen resistance is mediated by anchoring protein AKAP13

Cristiane Bentin Toaldo1, Xanthippi Alexi2, Karin Beelen3

  • 1Division of Molecular Pathology, the Netherlands Cancer Institute, Amsterdam, The Netherlands. c.bentin.toaldo@nki.nl.

BMC Cancer
|August 15, 2015
PubMed
Abstract

Insights

AKAP13 is essential for tamoxifen resistance in breast cancer by enabling Protein Kinase A (PKA) to phosphorylate Estrogen Receptor alpha (ERα). This AKAP13-PKA-ERα interaction leads to tamoxifen resistance in patients and cell lines.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Estrogen Receptor alpha (ERα)-positive breast cancer is treated with tamoxifen, but resistance is common.
  • Tamoxifen resistance is linked to Protein Kinase A (PKA) pathway activation, phosphorylating ERα at Serine 305.
  • The protein complexes mediating PKA-ERα interaction for ERα Serine 305 phosphorylation remain unclear.

Purpose of the Study:

  • To identify protein complexes involved in PKA-mediated ERα phosphorylation.
  • To investigate the role of these complexes in tamoxifen resistance.
  • To explore potential therapeutic targets for overcoming tamoxifen resistance.

Main Methods:

  • Immunohistochemistry on patient tumors to detect ERα Serine 305 phosphorylation.
  • Gene expression analysis (Agilent 44K) integrated with clinical data.
  • In vitro studies using MCF7 cells: immunoprecipitation, Fluorescence Resonance Energy Transfer (FRET), and siRNA knockdown.

Main Results:

  • AKAP13 gene network identified, with AKAP13 mRNA levels correlating with poor outcome and ERα Serine 305 phosphorylation in tamoxifen-treated patients.
  • AKAP13 interacts with both ERα and a PKA regulatory subunit in breast cancer cells.
  • AKAP13 knockdown inhibited PKA-mediated ERα phosphorylation and abrogated tamoxifen resistance.

Conclusions:

  • The PKA-anchoring protein AKAP13 is essential for ERα phosphorylation at Serine 305.
  • AKAP13 plays a critical role in mediating tamoxifen resistance in both cell lines and patient tumors.
  • AKAP13 represents a potential therapeutic target for overcoming tamoxifen resistance in breast cancer.

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