Downregulation Of Foxo3a By Dnmt1 Promotes Breast Cancer Stem Cell Properties And Tumorigenesis

Breast cancer stem cells (BCSCs) are tumor initiating cells that can self-renew and are highly tumorigenic and chemoresistant. Recent evidence indicated that FOXO3a plays an important role in regulating CSCs properties. However, the biologic function and detailed molecular mechanism of FOXO3a in BCSCs remains largely elusive. Here, we demonstrated that FOXO3a was hypermethylated and downregulated in breast cancer cells and tissues. Overexpression of FOXO3a potently attenuated the BCSCs properties in vitro and inhibited tumorigenesis in vivo, whereas knockdown of FOXO3a increased these properties. Further mechanistic investigation revealed that FOXO3a was functionally linked to the inhibition of the FOXM1/SOX2 pathway. Moreover, we found that SOX2 directly transactivated DNMT1 gene expression and then feedback inhibited FOXO3a expression. Clinically, we observed a significant inverse correlation between FOXO3a and FOXM1 or SOX2 expression levels. Loss of FOXO3a expression also predicted poor prognosis in breast cancer. In addition, we demonstrated that inhibition of DNMT activity suppressed tumor growth via regulating of FOXO3a/FOXM1/SOX2 signaling in breast cancer. Our findings suggest an important role of DNMT1/FOXO3a/FOXM1/SOX2 pathway in regulating BCSCs properties, identifying potential therapeutic targets for breast cancer. Keywords: breast cancer, cancer stem cell, FOXO3a, DNMT Note: This abstract was not presented at the meeting. Citation Format: Zhimin He, Hao Liu, Ying Song, Guopei Zheng. Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3677.