ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy

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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

Martina Antonelli1,2, Flavie Strappazzon1, Ivan Arisi3

  • 1Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.

Oncotarget
|April 21, 2017
PubMed

Insights

Ataxia-Telangiectasia Mutated (ATM) kinase sustains cancer stem-like cells by regulating autophagy-related gene ATG4C. Targeting ATM and ATG4C may improve eradication of breast cancer stem cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The role of Ataxia-Telangiectasia Mutated (ATM) kinase in cancer is complex, with emerging functions beyond its tumor suppressor gene status.
  • ATM has been shown to promote tumor progression in HER2-positive breast cancer.
  • Understanding ATM's multifaceted roles is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the role of ATM in maintaining stem-like cell phenotypes in breast cancer.
  • To explore the relationship between ATM expression and autophagy regulation in cancer stem cells.
  • To identify potential therapeutic targets for eradicating cancer stem cells.

Main Methods:

  • Mammosphere formation assays to measure stem-like cell populations.
  • Transcriptomic analysis to identify ATM-modulated genes.
  • Gene silencing and ectopic expression experiments to assess gene function.
  • Analysis of public tumor array data for ATM and ATG4C expression correlation.

Main Results:

  • ATM expression sustains a stem-like cell phenotype, measured by mammosphere formation, independent of HER2 levels.
  • ATM modulates cell cycle, DNA repair, and autophagy genes in mammospheres.
  • Silencing ATG4C impairs mammosphere formation, while its ectopic expression rescues growth in ATM-silenced cells.
  • ATM and ATG4C expression are correlated in most human breast cancer subtypes, excluding basal-like.

Conclusions:

  • ATM kinase and autophagy regulation are interconnected in breast cancer.
  • ATM and ATG4C are essential for mammosphere formation, highlighting their role in breast cancer stem cells.
  • Targeting ATM and ATG4C presents a potential strategy to eliminate cancer stem cells.
Keywords:
ATG4ATM kinaseautophagybreast cancer stem cells (BCSCs)mammospheres

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