MYC Inhibition Depletes Cancer Stem-like Cells in Triple-Negative Breast Cancer.

Abstract

There is mounting evidence that cancer stem-like cells (CSC) are selectively enriched in residual tumors after anticancer therapies, which may account for tumor recurrence and metastasis by regenerating new tumors. Thus, there is a critical need to develop new therapeutic agents that can effectively eliminate drug-resistant CSCs and improve the efficacy of cancer therapy. Here, we report that Triptolide (C1572), a small-molecule natural product, selectively depletes CSCs in a dose-dependent fashion in human triple-negative breast cancer (TNBC) cell lines. Nanomolar concentrations of C1572 markedly reduced c-MYC (MYC) protein levels via a proteasome-dependent mechanism. Silencing MYC expression phenocopied the CSC depletion effects of C1572 and induced senescence in TNBC cells. Limited dilution assays revealed that ex vivo treatment of TNBC cells with C1572 reduced CSC levels by 28-fold. In mouse xenograft models of human TNBC, administration of C1572 suppressed tumor growth and depleted CSCs in a manner correlated with diminished MYC expression in residual tumor tissues. Together, these new findings provide a preclinical proof of concept defining C1572 as a promising therapeutic agent to eradicate CSCs for drug-resistant TNBC treatment. Cancer Res; 77(23); 6641-50. ©2017 AACR.

• Authors: Aimin Yang, Shenghui Qin, Bradley A Schulte, Stephen P Ethier, Kenneth D Tew, Gavin Y Wang
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 23 Pg. 6641-6650 (12 01 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28951456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Diterpenes
• Epoxy Compounds
• Phenanthrenes
• Proto-Oncogene Proteins c-myc
• RNA, Small Interfering
• triptolide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Proliferation (drug effects)
• Diterpenes (pharmacology)
• Drug Resistance, Neoplasm
• Epoxy Compounds (pharmacology)
• Female
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Neoplastic Stem Cells (drug effects)
• Phenanthrenes (pharmacology)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors, genetics)
• RNA Interference
• RNA, Small Interfering (genetics)
• Spheroids, Cellular
• Triple Negative Breast Neoplasms (drug therapy, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays