Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Tumor-initiating cells (TICs) or cancer stem-like cells (CSCs) are subpopulations within tumors responsible for cancer recurrence after therapy.
• Identifying key regulators of TIC/CSC maintenance is crucial for developing effective cancer therapeutics.
• Steroid receptor coactivator 3 (SRC-3) is frequently overexpressed in various cancers, promoting tumor initiation, proliferation, and metastasis.

Purpose of the Study:

• To investigate the role of SRC-3 in supporting the TIC/CSC state and inducing epithelial-to-mesenchymal transition (EMT).
• To evaluate the efficacy of a small-molecule inhibitor (SI-2) targeting SRC-3 and SRC-1 in eliminating CSC/TIC populations.

Main Methods:

• Investigated SRC-3's role in maintaining the CSC state and inducing EMT.
• Assessed the impact of SI-2, a SRC-3/SRC-1 inhibitor, on CSC/TIC populations both in vitro and in vivo.

Main Results:

• SRC-3 was found to support the TIC/CSC state and induce EMT by upregulating master EMT regulators and stem cell markers.
• Inhibition of SRC-3 and SRC-1 using SI-2 effectively targeted CSC/TIC populations in both in vitro and in vivo models.
• SRC coactivators were identified as regulators of stem-like capacity in cancer cells.

Conclusions:

• SRC coactivators, including SRC-3, play a significant role in maintaining stem-like properties in cancer cells.
• Targeting SRC coactivators, such as SRC-3 and SRC-1, with inhibitors like SI-2 presents a promising therapeutic strategy to prevent cancer recurrence.