Targeting mTOR and Its Associated Signaling to Induce Cell Death in Breast Cancer Stem Cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Breast cancer (BC) is a leading cause of cancer-related deaths, with metastasis and relapse often driven by cancer stem cells (CSCs).
• The mTOR signaling pathway, along with AKT, is crucial for CSC maintenance and survival in various cancers, including breast cancer.

Purpose of the Study:

• To investigate the therapeutic potential of targeting the mTOR/AKT signaling pathway in breast cancer models.
• To evaluate the effects of the dual mTOR inhibitor Torin-2 on breast cancer cell death, proliferation, and stemness.

Main Methods:

• Utilized 2D and 3D breast cancer cell models.
• Treated cells with Torin-2, a dual inhibitor of mTORC1 and mTORC2.
• Assessed cell proliferation, apoptosis, autophagy markers (LC3II/I), AKT activity, translational machinery components (4EBP1, eIF4E, p70S6K), and stem cell marker ALDH expression.

Main Results:

• Torin-2 suppressed cell proliferation and induced mitochondrial apoptosis.
• Inhibition of mTOR decreased AKT activity and downregulated key translational factors.
• Torin-2 activated autophagy signaling, evidenced by increased LC3II/I.
• Torin-2 treatment reduced ALDH expression in breast cancer spheroids, indicating suppressed stemness.

Conclusions:

• Dual inhibition of mTORC1 and mTORC2 by Torin-2 demonstrates significant antitumor activity against breast cancer.
• Targeting the mTOR/AKT pathway with Torin-2 effectively suppresses breast cancer cell growth, survival, and stemness in both 2D and 3D models.