Sicheng Liu, Ping Deng, Chengmeng Liu, Huihui Hong, Qixue Zheng, Jinxian Lin, Jiayi Li, Zhulin Du, Lingling Yang, Kun Luo, Haiyan Yu, Zhengwei Liang, Zhengping Yu, Huifeng Pi, Zhou Zhou
Abstract
Introduction
Bisphenol S (BPS), a substitute for bisphenol A (BPA), serves as an endocrine disruptor implicated in breast cancer (BC) progression, but its mechanisms remain unclear.
Objectives
This study aimed to elucidate the underlying mechanisms of BPS effects on BC metastasis through
in vivo and
in vitro experiments.
Methods
Transgenic MMTV-Erbb2 mice that spontaneously developed breast tumors were orally administered BPS (50 μg/L) for 19 weeks, and BC cells were exposed to BPS (0, 0.01, 0.1, or 1 μM) for 72 h to examine the effects of BPS exposure on the migration and invasion of BC cells. Furthermore, we employed transcriptomics, KEGG enrichment analysis and Comparative Toxicogenomics Database (CTD) predictions to explore the potential mechanisms underlying BPS −induced BC metastasis. In addition, we used tissue microarray (TMA) and public databases to reveal DRD2′s critical role in BC progression.
Results
Our results indicated that low-dose BPS (50 μg/L, approximately 6.14 μg/kg/day) facilitated BC metastasis both
in vitro and
in vivo. Transcriptomic analysis identified DRD2 as a critical regulator of migration and invasion in BPS-exposed MCF-7 cells. Furthermore, KEGG enrichment analysis coupled with the CTD demonstrated that BPS enhanced the migration and invasion of BC cells via the Akt/GSK3β signaling pathway activation. Importantly, DRD2 overexpression apparently blocked the Akt/GSK3β pathway, effectively reversing BPS-induced metastasis of BC both
in vitro and
in vivo. Intriguingly, TMA and public database analyses revealed a marked decrease of DRD2 levels in BC tissues, which were inversely correlated with p-Akt levels in BC tissues and positively associated with the poor clinical characteristics of BC patients.
Conclusion
BPS exposure reduces DRD2 levels, activating Akt/GSK3β signaling to drive BC metastasis. These findings highlight the risk of BPS as a BPA alternative and unravel mechanistic insights into the role of environmental endocrine disruptors in cancer progression.
