Bisphenols exposure at environmentally relevant dose promoted ovarian cancer progression and modulated tumor microenvironment through β-catenin/SPP1 axis

Abstract

Bisphenol A (BPA) and its substitute, Bisphenol S (BPS) are typical endocrine-disrupting chemicals used in plastics, but their cancer-promoting effect has remained controversial. Here, we investigated the effects of environmentally relevant doses of BPA/BPS exposure on the tumor microenvironment (TME) in ovarian cancer. BPA exposure levels was exhibiting a declining trend and BPS showing an ascending trend in the female population by analyzing the NHANES data (2013-2016). Low doses of BPA/BPS both significantly promoted the migration and invasion of ovarian cancer cells in a dose-dependent manner by activating the Wnt/β-catenin signaling pathway, thereby facilitating the SPP1 gene transcription. Notably, low-dose BPA/BPS exposure stimulated ovarian cancer cells to secrete OPN protein (coded by the SPP1 gene), subsequently inducing the transformation of fibroblasts into cancer-associated fibroblasts (CAFs), which could reshape the TME of ovarian cancer. Two in-vivo experiments established with nude mice and SPP1^-/- mice respectively, both confirmed that low-dose BPA/BPS exposure increased the incidence of tumor metastasis accompanied by CAF infiltration, while administration of OPN-neutralizing antibodies effectively blocked these effects. Our results indicated that exposure to either BPA or its substitute BPS could promote the release of secreted protein OPN via the β-catenin/SPP1 axis, ultimately modulating the TME and enhancing the progression of ovarian cancer, providing new evidence and potential intervention strategies for the toxicological assessment and management of bisphenols.