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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
09:08

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Published on: January 12, 2020

Crosstalk between PKCα and Notch-4 in endocrine-resistant breast cancer cells

J Yun1, A Pannuti, I Espinoza

  • 1Cardinal Bernardin Cancer Center and Department of Pathology, Loyola University Chicago, Maywood, IL, USA.

Oncogenesis
|August 7, 2013
PubMed

Insights

Protein kinase Cα (PKCα) overexpression drives tamoxifen-resistant breast cancer by increasing Notch-4 signaling. Inhibiting Notch pathway shows promise for treating endocrine-resistant breast cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The Notch pathway is crucial in breast cancer, influencing estrogen independence and stem-like cell properties.
  • Protein kinase Cα (PKCα) overexpression is linked to endocrine-resistant breast cancers and tamoxifen resistance.
  • Estrogen receptor α (ERα)+ breast cancer cells with estrogen-independent phenotypes exhibit higher Notch activity.

Purpose of the Study:

  • To investigate if PKCα overexpression impacts Notch activity.
  • To determine if Notch signaling contributes to endocrine resistance in PKCα-overexpressing breast cancer cells.

Main Methods:

  • Analysis of published microarray data and archival breast carcinoma specimens.
  • Real-time reverse transcription PCR and immunohistochemistry.
  • In vitro and in vivo studies using tamoxifen-resistant T47D cell models and xenografts.
  • Notch-4 knockdown and Notch-4 intracellular domain (Notch-4IC) expression experiments.
  • Gene expression profiling and treatment with a γ-secretase inhibitor.

Main Results:

  • PKCα expression correlates with Notch-4 in ERα+ breast carcinomas.
  • PKCα overexpression selectively increases Notch-4 expression via activator protein-1 (AP-1) in tamoxifen-resistant cells.
  • Notch-4 promotes estrogen-independent, tamoxifen-resistant growth and induces pathways associated with endocrine and chemoresistance.
  • A γ-secretase inhibitor reduced tumor growth in PKCα-overexpressing xenografts, alone and with tamoxifen.

Conclusions:

  • PKCα overexpression induces Notch-4, which drives endocrine-resistant breast cancer growth.
  • Notch-4 activates multiple resistance pathways, suggesting it as a therapeutic target.
  • Notch inhibitors warrant clinical evaluation for endocrine-resistant breast cancers with high PKCα and Notch-4 expression.

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