Estrogen insensitivity syndrome: the ‘Upside Down’ of ESR1 mutations

The estrogen receptor α (ERα) is a central regulator of 17β-estradiol (E2)-dependent physiological processes in reproductive and non-reproductive tissues. Deregulation of ERα signaling underlies distinct human pathologies, including breast cancer (BC) and the rare genetic disorder called estrogen insensitivity syndrome (EIS). In BC, somatic mutations of ESR1, the gene encoding ERα, emerge under endocrine therapy (ET) pressure and promote ligand-independent receptor activation, driving endocrine resistance and disease progression. In contrast, germline ESR1 mutations cause EIS by impairing ERα function and rendering peripheral tissues insensitive to circulating E2. Here, we review the structural and functional consequences of germline ERα point mutations identified in EIS and compare them with somatic ERα mutations described in BC. Despite their opposite effects on receptor activation, both classes of mutations disrupt distinct layers of ERα signaling, including ligand binding, DNA interaction, coactivator recruitment, nuclear trafficking, transcriptional regulation, and potentially extranuclear signaling. This comparative analysis reveals that perturbation of different mechanistic nodes within the ERα signaling network can converge on a shared phenotype of resistance. The results reviewed here underscore the modular nature of ERα signaling and highlight how structurally and mechanistically diverse mutations can produce convergent pathological phenotypes, providing insights into the generation of resistant ERα across distinct disease contexts.