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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Notch1 regulates Orai1 and Orai3 expression in breast cancer cells

Joel Nieto-Felipe1, Alvaro Macias-Diaz1, Sandra Alvarado1

  • 1Department of Physiology (Cellular Physiology Research Group) Institute of Molecular Pathology Biomarkers (IMPB) , Universidad de Extremadura , Caceres, 10003, Spain.

Scientific Reports
|December 18, 2025
PubMed

Insights

Notch1 signaling regulates Orai1 and Orai3 expression in breast cancer cells, impacting store-operated calcium entry (SOCE). This Notch1-HEY1-Orai axis offers potential for subtype-specific breast cancer therapies.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Calcium Signaling

Background:

  • Store-operated calcium entry (SOCE) is crucial for cellular functions, and its dysregulation is linked to pathologies like cancer.
  • Orai channels mediate SOCE, and their altered expression/function contributes to cancer development.
  • Notch1 signaling is implicated in breast cancer progression, with known alterations in Orai function.

Purpose of the Study:

  • To investigate the role of Notch1 signaling in regulating Orai1 and Orai3 expression in breast cancer.
  • To explore the impact of Notch1-mediated Orai modulation on SOCE in different breast cancer subtypes.
  • To elucidate the Notch1-HEY1-Orai axis in breast cancer pathogenesis.

Main Methods:

  • Utilized expression of active Notch1 and Jagged-1 (Jag-1) agonist in breast cancer cell lines.
  • Employed DAPT, a γ-secretase inhibitor, to block Notch1 pathway activation.
  • Assessed Orai1/Orai3 expression and SOCE changes following Notch1 pathway modulation.
  • Investigated the role of HEY1 and its mutants (HEY1-S68A, HEY1-S68D) in mediating Notch1 effects.

Main Results:

  • Notch1 demonstrated a differential regulatory role on Orai1 and Orai3 expression in non-tumoral versus cancerous breast cells.
  • Notch1 activation modulated Orai1 and Orai3 expression, which correlated with altered SOCE.
  • HEY1 mimicked Notch1's effect on Orai expression, while the phosphomimetic HEY1-S68D mutant did not.

Conclusions:

  • The Notch1-HEY1-Orai axis plays a significant role in regulating Orai expression and SOCE in breast cancer.
  • Understanding this axis may lead to subtype-specific therapeutic strategies for breast cancer.
  • Targeting the Notch1-HEY1-Orai pathway could offer novel approaches for breast cancer treatment.
Keywords:
Notch1Orai1Orai3Store-operated Ca2+ entry

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