More than alternative estrogen receptors: the emerging role of GPER-1 and ERα36 in breast cancer.

Breast cancer classification and therapeutic decision-making have traditionally relied on the evaluation of estrogen receptor alpha (ERα), PR, and HER2, yet this framework does not fully explain tumor heterogeneity, endocrine resistance, or estrogen responsiveness in ERα-negative contexts. Emerging evidence implicates non-genomic estrogen signaling mediated by membrane-associated receptors such as G protein-coupled estrogen receptor 1 (GPER-1) and ERα36. Acting as interconnected signaling nodes, these receptors activate MAPK/ERK and PI3K/AKT pathways and engage in crosstalk with receptors such as EGFR, promoting proliferation, cellular plasticity, and adaptive responses. Here, we propose an integrative framework based on three axes: endocrine resistance in ERα-positive tumors, estrogen responsiveness in ERα-negative subtypes, and environmental modulation of signaling. Within this model, GPER-1 and ERα36 form a coordinated network that extends beyond genomic mechanisms and converges on shared downstream effectors. These pathways also intersect with post-transcriptional regulation, tumor-microenvironment interactions, and extracellular vesicle-mediated communication, contributing to tumor progression and metastasis. Environmental ligands, such as bisphenol A, may further modulate signaling intensity, reinforcing plasticity and resistance phenotypes. Collectively, GPER-1 and ERα36 emerge as candidate biomarkers with diagnostic and therapeutic relevance. Their integration into multi-omics and functional classification strategies may refine breast cancer stratification and support more precise therapeutic approaches.