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

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.