Abstract
Tumor-initiating cells (TIC) represent cancer stem-like cell (CSC) subpopulations within tumors that are thought to give rise to recurrent cancer after therapy. Identifying key regulators of TIC/CSC maintenance is essential for the development of therapeutics designed to limit recurrence. The steroid receptor coactivator 3 (SRC-3) is overexpressed in a wide range of cancers, driving tumor initiation, cell proliferation, and metastasis. Here we report that SRC-3 supports the TIC/CSC state and induces an epithelial-to-mesenchymal transition (EMT) by driving expression of the master EMT regulators and stem cell markers. We also show that inhibition of SRC-3 and SRC-1 with SI-2, a second-generation SRC-3/SRC-1 small-molecule inhibitor, targets the CSC/TIC population both in vitro and in vivo Collectively, these results identify SRC coactivators as regulators of stem-like capacity in cancer cells and that these coactivators can serve as potential therapeutic targets to prevent the recurrence of cancer. Cancer Res; 77(16); 4293-304. ©2017 AACR.