Bisphenol A-induced cancer-associated adipocytes promotes breast carcinogenesis via CXCL12/AKT signaling.

Bisphenol A (BPA), a commonly used plastic additive, is believed to cause obesity. As an environmental endocrine disruptor, BPA is closely associated with the onset and progression of BC. However, the molecular mechanisms underlying the promotion of breast cancer by BPA remain unclear. As obesity is a significant risk factor for breast cancer, this study aimed at exploring whether BPA facilitates the progression of breast cancer by inducing obesity. Using the National Health and Nutrition Examination Survey data, a positive correlation was observed between BPA exposure and the risk of sex-specific cancers among US adults with body mass index ≥30, suggesting that obesity may be influenced by urinary BPA. 3T3-L1 cells differentiated into mature adipocytes following treatment with 10 M BPA, and subsequent treatment with 4T1-conditioned medium acquired properties associated with cancer-associated adipocytes (CAAs). Network pharmacology suggested that CXCL12 may serve as a key target gene in breast cancer progression. Follow-up PCR analysis revealed high CXCL12 expression in BPA-induced CAAs. Overexpression of CXCL12 promoted epithelial-mesenchymal transition (EMT) and 4T1 cell migration by activating the AKT pathway. In vivo, BPA-induced CAAs accelerated tumor growth compared to a controls xenografted with only 4T1 cells. In tissues from the BPA-CAAs group, the expression of CXCL12, markers associated with CAAs, phosphorylated AKT, N-cadherin, and vimentin was markedly elevated, whereas the expression of E-cadherin was reduced. In conclusion, BPA may induce adipose cells to differentiate into CAA-like cells and subsequently advance breast cancer EMT through the CXCL12/AKT pathway.