Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and β-catenin

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Aberrant activation of the eukaryotic initiation factor 4E (eIF4E) signaling pathway is a hallmark of breast cancer.
• Targeting this pathway offers potential therapeutic strategies for breast cancer treatment.

Purpose of the Study:

• To investigate the efficacy of galeterone, a drug in clinical trials for prostate cancer, against breast cancer.
• To elucidate the underlying molecular mechanisms of galeterone's action in breast cancer cells.

Main Methods:

• Treatment of diverse breast cancer cell lines and a xenograft mouse model with galeterone.
• Assessment of cell viability, proliferation, migration, and protein levels (MNK1/2, phosphorylated eIF4E, β-catenin, GSK-3β, Akt).
• Combination studies with standard chemotherapeutic drugs and rescue experiments.

Main Results:

• Galeterone significantly reduced breast cancer cell viability, proliferation, and migration at nanomolar concentrations, independent of subtype or mutations.
• Galeterone enhanced the efficacy of chemotherapeutic drugs in reducing proliferation and viability.
• Mechanism analysis revealed galeterone suppresses MNK1/2 and eIF4E phosphorylation, and promotes β-catenin degradation via GSK-3β/Akt signaling.

Conclusions:

• Galeterone demonstrates potent anti-breast cancer activity through dual inhibition of MNK/eIF4E and β-catenin pathways.
• Galeterone shows preclinical efficacy as a single agent and in combination with chemotherapy, supporting its clinical investigation for breast cancer.