2. Academic Validation
  3. Bisphenol S drives breast cancer metastasis by inhibiting dopamine receptor D2 to activate the Akt/GSK3β oncogenic axis

Bisphenol S drives breast cancer metastasis by inhibiting dopamine receptor D2 to activate the Akt/GSK3β oncogenic axis

  • J Adv Res. 2025 Sep 23:S2090-1232(25)00744-1. doi: 10.1016/j.jare.2025.09.045.
Sicheng Liu 1,  Ping Deng 2,  Chengmeng Liu 3,  Huihui Hong 4,  Qixue Zheng 5,  Jinxian Lin 6,  Jiayi Li 7,  Zhulin Du 8,  Lingling Yang 9,  Kun Luo 10,  Haiyan Yu 11,  Zhengwei Liang 12,  Zhengping Yu 13,  Huifeng Pi 14,  Zhou Zhou 15
Affiliations

Affiliations

  • 1 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: liuscmail0701@163.com.
  • 2 Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: dengping@tmmu.edu.cn.
  • 3 Department of Operating Theater, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province 412000, China. Electronic address: 13487730178@163.com.
  • 4 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: huihh1217@cqu.edu.cn.
  • 5 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: zhengqxmail@163.com.
  • 6 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: 1492941001@qq.com.
  • 7 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: lijiayi200208@163.com.
  • 8 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: 1137998334@qq.com.
  • 9 Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: yanglingling_2010@163.com.
  • 10 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: 984191567@qq.com.
  • 11 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: 1436338292@qq.com.
  • 12 Department of Otolaryngology, Chongqing General Hospital, Chongqing University, Chongqing 401147, China. Electronic address: 813119066@qq.com.
  • 13 Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: yuzping_tmmu@126.com.
  • 14 Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: pihuifeng@tmmu.edu.cn.
  • 15 Department of Environmental Medicine, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: lunazhou00@cqu.edu.cn.
PMID: 40998253 DOI: 10.1016/j.jare.2025.09.045
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.

Keywords

Akt/GSK3β signaling; Bisphenol S; Breast cancer; DRD2; Metastasis.

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