Tumor-associated macrophages suppress estrogen receptor-β expression in triple-negative breast cancer through the PI3K/AKT pathway

Triple-negative breast Cancer (TNBC) is a highly aggressive breast Cancer subtype with limited therapeutic options. Estrogen receptor (ER)-β exerts anti-tumor effects. However, ERβ expression is frequently reduced in TNBC and the mechanisms underlying the downregulation of ERβ in TNBC remain poorly understood. In the present study, findings revealed that tumor-associated macrophages (TAMs), which are abundant in the tumor microenvironment, suppressed ERβ expression in TNBC cells. The relationship between TAMs and ERβ in TNBC was investigated through bioinformatics analysis, co-culture and orthotopic mouse models. ERβ expression levels were lower in the TNBC tumors compared with normal tissues. Mechanistically, TAM-induced activation of the PI3K/Akt pathway suppressed ERβ expression by reducing FOXO3a binding to the ESR2 promoter, whereas inhibition of PI3K/Akt restored ERβ expression. Notably, combined PI3K/Akt pathway inhibition with ERβ activation attenuated TNBC cell metastasis. Overall, findings indicated that TAMs promoted TNBC progression by downregulating ERβ expression through the PI3K/Akt/FOXO3a axis, highlighting the therapeutic potential of combining PI3K/Akt inhibitors with ERβ agonists in TNBC.

ERβ; PI3K/AKT pathway; mouse model; triple-negative breast cancer; tumor-associated macrophages.