Triclocarban and triclosan promote breast cancer progression in vitro and in vivo via activating G protein-coupled estrogen receptor signaling pathways

Ting-Ting He; Xin Li; Jie-Zhi Ma; Yuan Yang; Shiye Zhu; Jianhua Zeng; Lin Luo; Yu-Long Yin; Lin-Ying Cao

doi:10.1016/j.scitotenv.2024.172782

Triclocarban and triclosan promote breast cancer progression in vitro and in vivo via activating G protein-coupled estrogen receptor signaling pathways

Sci Total Environ. 2024 Apr 26:931:172782. doi: 10.1016/j.scitotenv.2024.172782. Online ahead of print.

Authors

Ting-Ting He¹, Xin Li¹, Jie-Zhi Ma², Yuan Yang¹, Shiye Zhu¹, Jianhua Zeng³, Lin Luo¹, Yu-Long Yin¹, Lin-Ying Cao⁴

Affiliations

¹ College of Environment and Ecology, Hunan Agricultural University, Changsha 410128, China.
² Department of Obstetrics and Gynecology, Xiangya Third Hospital, Central South University, Changsha 410013, China.
³ College of Food Science and Engineering, Ocean University of China, Qingdao 266000, China.
⁴ College of Environment and Ecology, Hunan Agricultural University, Changsha 410128, China. Electronic address: caolinying226@hunau.edu.cn.

PMID: 38679099
DOI: 10.1016/j.scitotenv.2024.172782

Abstract

Triclocarban (TCC) and triclosan (TCS) have been detected ubiquitously in human body and evoked increasing concerns. This study aimed to reveal the induction risks of TCC and TCS on triple negative breast cancer through non-genomic GPER-mediated signaling pathways. Molecular simulation indicated that TCC exhibited higher GPER binding affinity than TCS theoretically. Calcium mobilization assay displayed that TCC/TCS activated GPER signaling pathway with the lowest observed effective concentrations (LOEC) of 10 nM/100 nM. TCC and TCS also upregulated MMP-2/9, EGFR, MAPK3 but downregulated MAPK8 via GPER-mediated signaling pathway. Proliferation assay showed that TCC/TCS induced 4 T1 breast cancer cells proliferation with the LOEC of 100 nM/1000 nM. Wound-healing and transwell assays showed that TCC/TCS promoted 4 T1 cells migration in a concentration-dependent manner with the LOEC of 10 nM. The effects of TCC on breast cancer cells proliferation and migration were stronger than TCS and both were regulated by GPER. TCC/TCS induced migratory effects were more significantly than proliferative effect. Mechanism study showed that TCC/TCS downregulated the expression of epithelial marker (E-cadherin) but upregulated mesenchymal markers (snail and N-cadherin), which was reversed by GPER inhibitor G15. These biomarkers results indicated that TCC/TCS-induced 4 T1 cells migration was a classic epithelial to mesenchymal transition mechanism regulated by GPER signaling pathway. Orthotopic tumor model verified that TCC promoted breast cancer in-situ tumor growth and distal tissue metastasis via GPER-mediated signaling pathway at human-exposure level of 10 mg/kg/d. TCC-induced tissue metastasis of breast cancer was more significantly than in-situ tumor growth. Overall, we demonstrated for the first time that TCC/TCS could activate the GPER signaling pathways to induce breast cancer progression.

Keywords: Breast cancer; Estrogenic disruption; G protein-coupled estrogen receptor; Triclocarban; Triclosan.