Metformin reduces senescence induced by obesity-related inflammation in luminal breast cancer through estrogen receptor beta modulation

Obesity contributes to worse outcomes in breast cancer, particularly in the luminal subtype, where cellular senescence could increase tumor aggressiveness. Parallelly, Estrogen Receptor Beta (ERβ) has emerged as an important mediator in the cellular response to obesity-associated inflammation that metformin could counteract. This study explores metformin's role in targeting senescence to mitigate obesity-induced tumor progression. Using the GSE189757 dataset, differentially expressed genes in obese versus lean luminal breast cancer patients were examined by in silico analysis. T47D, BT474, and MCF7 cell lines were treated with an obesity-related inflammatory cocktail (ELIT) and metformin. Protein levels, mRNA expression and functional assays assessed mitochondrial activity, oxidative stress, cell viability, and senescence-related markers. The role of ERβ was investigated through gene silencing, gene overexpression, and correlation studies using datasets. Experimental results show that ELIT exposure increased mitochondrial activity, oxidative stress, and senescence markers, particularly in T47D cells, effects that metformin mitigated. Metformin also reduced SASP-related gene expression, thereby limiting autocrine signaling effects on migration, mammosphere formation, and drug sensitivity. ERβ expression was observed as a potential modulator of ELIT-induced alterations, and metformin reduced its expression. Analysis of patient datasets revealed a positive correlation between ERβ gene (ESR2) expression and senescence-related markers in obese luminal breast cancer patients, particularly MCL1, BCL2L1, CCL2, and ICAM1. These findings indicate that ERβ exhibits a key role as mediator of obesity-induced tumor alterations by promoting senescence-related markers, and that metformin's ability to target ERβ offers a potential strategy to suppress senescence-driven malignancy and improve therapeutic outcomes of obese luminal breast cancer patients.