Actinomycin D Down-regulates SOX2 Expression and Induces Death in Breast Cancer Stem Cells

Abstract

Background/aim: One of the major hurdles in the treatment of breast cancers is the inability of anti-cancer drugs to eliminate the breast cancer stem cells (BCSCs) population, which leads to disease relapse. The dearth in anti-cancer drugs that target BCSCs can be attributed to the absence of in vitro screening models that can not only recapitulate the tumor microenvironment consisting of BCSCs but also preserve the 3-dimensional (3D) architecture of in vivo tumors.

Materials and methods: In our present study, we have developed a 3D cell culture system that shows: (i) enrichment of BCSCs, (ii) increased drug resistance, and (iii) generation of hypoxic conditions similar to tumors.

Results: Using this model, we were able to screen a FDA-approved diversity set and identify as well as validate actinomycin D as a potential anti-breast cancer agent. Interestingly, we show that actinomycin D specifically targets and down-regulates the expression of the stem cell transcription factor, Sox-2. Additionally, down-regulation of Sox-2 leads to depletion of the stem-cell population resulting in the inability of breast cancer cells to initiate tumor progression.

Conclusion: This study demonstrates the utility of an in vivo-like 3D cell culture system for the identification and validation of anti-cancer agents that will have a better probability of success in the clinic.

Keywords: Actinomycin D; SOX2; breast cancer; cancer stem cells; tumoroids.