Abstract
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 via downregulating the DNA methylation level of PTEN. Moreover, apoptosis was induced via the activation of PI3K-AKT downstream TSC1 and the downregulation of methylation levels of DAXX, TNF, FADD and CASP8 etc. These findings indicated 6-TG exerts its anti-tumor effects in vitro and in vivo 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.
Highlights
Triple-negative breast cancer (TNBC) is a breast cancer subtype that does not clinically express significant levels of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), representing only 15–20% of breast cancer cases [1,2,3]
Cluster B is a TNBC-specific cluster containing 354 genes, which are mainly related to pathways such as focal adhesion, PI3K–AKT signaling, human papillomavirus infection, human T-cell leukemia virus 1 infection
Based on the summarized data, we propose that some drugs targeting leukemia might have a similar role in inhibiting TNBC progression
Summary
TNBC is a breast cancer subtype that does not clinically express significant levels of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), representing only 15–20% of breast cancer cases [1,2,3]. TNBC is the most aggressive breast cancer type without any approved targeted therapy [4, 5]. Chemotherapies are the only therapeutic treatment for TNBC. Drug repurposing and repositioning have attracted increasing attention in recent years [6, 7], such as thalidomide, a drug for morning sickness but currently is used for the treatment of multiple myeloma [8]. Exploration of effective drug selection strategy for TNBC has become increasingly important. Recent studies have attempted to find the tumor pathogenesis through high throughput sequencing, but the integration of transcriptome maps of various tumors for drug discovery remains slow
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