{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:04:27Z","timestamp":1790355867239,"version":"4.1.0"},"reference-count":55,"publisher":"Bioscientifica","issue":"3","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The estrogen receptor \u03b1 (ER\u03b1) is a central regulator of 17\u03b2-estradiol (E2)-dependent physiological processes in reproductive and non-reproductive tissues. Deregulation of ER\u03b1 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 ER\u03b1, 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 ER\u03b1 function and rendering peripheral tissues insensitive to circulating E2. Here, we review the structural and functional consequences of germline ER\u03b1 point mutations identified in EIS and compare them with somatic ER\u03b1 mutations described in BC. Despite their opposite effects on receptor activation, both classes of mutations disrupt distinct layers of ER\u03b1 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 ER\u03b1 signaling network can converge on a shared phenotype of resistance. The results reviewed here underscore the modular nature of ER\u03b1 signaling and highlight how structurally and mechanistically diverse mutations can produce convergent pathological phenotypes, providing insights into the generation of resistant ER\u03b1 across distinct disease contexts.<\/jats:p>","DOI":"10.1530\/joe-26-0117","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:32:03Z","timestamp":1789381923000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":0,"title":["Estrogen insensitivity syndrome: the \u2018Upside Down\u2019 of\n                    <i>ESR1<\/i>\n                    mutations"],"prefix":"10.1530","volume":"270","author":[{"given":"Claudia","family":"Bellucci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Cipolletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9535-5405","authenticated-orcid":true,"given":"Sergio","family":"Vulterini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4651-2509","authenticated-orcid":true,"given":"Filippo","family":"Acconcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"2026092512114931700_bib1","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.3390\/cancers13071583","article-title":"A tale of ice and fire: the dual role for 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