Data from The Role of Forkhead Box Q1 Transcription Factor in Anticancer Effects of Withaferin A in Breast Cancer

Abstract

<div>Abstract<p>Elimination of both rapidly dividing epithelial mammary cancer cells as well as breast cancer stem-like cells (bCSC) is essential for maximizing antitumor response. Withaferin A (WA), a small molecule derived from a medicinal plant (<i>Withania somnifera</i>), is highly effective in reducing burden and/or incidence of breast cancer <i>in vivo</i> in various preclinical models. We have shown previously that suppression of breast cancer incidence by WA administration in a rat model is associated with a decrease in self-renewal of bCSC but the underlying mechanism is still elusive. This study investigated the role of forkhead box Q1 (FoxQ1) transcription factor in antitumor responses to WA. Exposure of MDA-MB-231 and SUM159 cells to WA resulted in downregulation of protein and mRNA levels of FoxQ1 as well as inhibition of its transcriptional activity. FoxQ1 overexpression in SUM159 and MCF-7 cells resulted in a marked protection against WA-mediated inhibition of bCSC as judged by flow cytometric analysis of CD49f<sup>high</sup> population and mammosphere assay. RNA-sequencing analysis revealed upregulation of many bCSC-associated genes by FoxQ1 overexpression in SUM159 cells, including <i>IL8</i> whose expression was decreased by WA treatment in SUM159 and MCF-7 cells. FoxQ1 was recruited to the promoter of <i>IL8</i> that was inhibited significantly by WA treatment. On the other hand, WA-mediated inhibition of cell proliferation or migration was not affected by FoxQ1 overexpression. The FoxQ1 overexpression partially attenuated WA-mediated G<sub>2</sub>–M phase cell cycle arrest in SUM159 cells only. These results indicate that FoxQ1 is a target of WA for inhibition of bCSC fraction.</p>Prevention Relevance:<p>Withaferin A (WA) is highly effective in reducing burden and/or incidence of breast cancer in various preclinical models. However, the mechanism underlying breast cancer prevention by WA is not fully understood. This study shows a role for FoxQ1 in antitumor response to WA.</p></div>