AUTHOR=Zhang Daoyu , An Xinglan , Li Qi , Man Xiaxia , Chu Meiran , Li Hao , Zhang Nan , Dai Xiangpeng , Yu Hao , Li Ziyi 

TITLE=Thioguanine Induces Apoptosis in Triple-Negative Breast Cancer by Regulating PI3K–AKT Pathway

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.524922

DOI=10.3389/fonc.2020.524922

ISSN=2234-943X

ABSTRACT=<p>Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of biological targets and poor sensitivity to conventional therapies. Chemotherapy is the main clinical therapy, but the effective screening strategy for chemotherapy drugs is poorly investigated. Drug repositioning has been the center of attention in recent years attracting numerous studies. Here, we firstly found multiple common features between leukemia and TNBC by analyzing the global transcriptome profiles based on the transformed comparison data from NCI60. Therefore, we investigated the role of the classic leukemia drug thioguanine (6-TG) in TNBC cancer cells. Our results indicated that 6-TG inhibited cell proliferation and tumor cell progression by suppressing PI3K–AKT pathway <italic>via</italic> downregulating the DNA methylation level of <italic>PTEN</italic>. Moreover, apoptosis was induced <italic>via</italic> the activation of PI3K-AKT downstream <italic>TSC1</italic> and the downregulation of methylation levels of <italic>DAXX</italic>, <italic>TNF</italic>, <italic>FADD</italic> and <italic>CASP8</italic><italic>etc.</italic> These findings indicated 6<italic>-</italic>TG exerts its anti-tumor effects <italic>in vitro</italic> and <italic>in vivo</italic> through regulating the DNA methylation levels of genes involved in PI3K–AKT and apoptosis pathway. Meanwhile, our study suggested that transcriptome-based drug screening has potential implications for breast cancer therapy and drug selection.</p>