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ATM kinase sustains HER2 tumorigenicity in breast cancer

Venturina Stagni1, Isabella Manni2, Veronica Oropallo1

  • 11] Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy [2] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.

Nature Communications
|April 17, 2015
PubMed

Insights

ATM kinase, typically a tumor suppressor, promotes HER2-positive breast cancer growth and recurrence by stabilizing HER2 protein. This challenges its traditional role and suggests ATM activity impacts treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ATM kinase is recognized for its role in maintaining genomic stability and acting as a tumor suppressor.
  • Emerging evidence suggests ATM participates in signaling networks, hinting at a more complex, potentially dual role in cancer.
  • The specific role of ATM in HER2-positive breast cancer, particularly its impact on tumorigenicity and patient outcomes, requires further elucidation.

Purpose of the Study:

  • To investigate the role of ATM expression and activity in HER2-dependent tumorigenicity.
  • To explore the correlation between ATM activation and clinical outcomes in patients with HER2-positive breast cancer.
  • To identify the molecular mechanisms by which ATM influences HER2 signaling and protein stability.

Main Methods:

  • In vitro and in vivo experiments to assess ATM's effect on HER2-dependent tumor growth.
  • Analysis of patient data to correlate ATM activation with time to recurrence in HER2-positive breast cancer.
  • Biochemical assays to determine ATM's interaction with HER2 and its effect on ubiquitination and degradation pathways, including its role with HSP90.

Main Results:

  • ATM expression and activity were found to promote HER2-dependent tumorigenicity both in vitro and in vivo.
  • A significant correlation was observed between ATM activation and a reduced time to recurrence in patients with invasive HER2-positive breast cancer.
  • ATM was identified as a novel modulator of HER2 protein stability, stabilizing HER2 by complexing it with HSP90, thereby preventing its ubiquitination and degradation.
  • ATM sustains AKT activation downstream of HER2, influencing key oncogenic signaling pathways.

Conclusions:

  • ATM exhibits a tumorigenic role in HER2-positive breast cancer, challenging its established function as solely a tumor suppressor.
  • ATM's modulation of HER2 protein stability and downstream signaling suggests it plays a critical role in HER2-driven tumorigenesis.
  • ATM activity status may serve as a prognostic and predictive biomarker for HER2-positive breast cancer, potentially informing therapeutic strategies.

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