{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T02:46:52Z","timestamp":1789267612916,"version":"build-2803163510"},"reference-count":182,"publisher":"Open Exploration Publishing","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Explor Target Antitumor Ther"],"accepted":{"date-parts":[[2026,5,17]]},"abstract":"<jats:p xml:lang=\"en\">Breast cancer classification and therapeutic decision-making have traditionally relied on the evaluation of estrogen receptor alpha (ER\u03b1), PR, and HER2, yet this framework does not fully explain tumor heterogeneity, endocrine resistance, or estrogen responsiveness in ER\u03b1-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 ER\u03b136. 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 ER\u03b1-positive tumors, estrogen responsiveness in ER\u03b1-negative subtypes, and environmental modulation of signaling. Within this model, GPER-1 and ER\u03b136 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 ER\u03b136 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.<\/jats:p>","DOI":"10.37349\/etat.2026.1002377","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:16:18Z","timestamp":1783314978000},"update-policy":"https:\/\/doi.org\/10.37349\/open_exploration_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["More than alternative estrogen receptors: the emerging role of GPER-1 and ER\u03b136 in breast cancer"],"prefix":"10.37349","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7599-6525","authenticated-orcid":false,"given":"Luis","family":"Molina Calistro","sequence":"first","affiliation":[{"name":"Facultad de Ciencias, Universidad San Sebasti\u00e1n, Lago Panguipulli 1390, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo Flavio","family":"Torres","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias, Universidad San Sebasti\u00e1n, Lago Panguipulli 1390, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johana","family":"Spies","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias, Universidad San Sebasti\u00e1n, Lago Panguipulli 1390, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia S\u00e1nchez","family":"Meneses","sequence":"additional","affiliation":[{"name":"Posgrado en Ciencias Biol\u00f3gicas UATx, Centro Tlaxcala Biolog\u00eda de la Conducta, Doctorado en Ciencias Biol\u00f3gicas, Universidad Aut\u00f3noma de Tlaxcala, Tlaxcala, Tlax 90800, M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Soto","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebasti\u00e1n, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Carrasco","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebasti\u00e1n, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javiera","family":"G\u00e1lvez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebasti\u00e1n, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayanara","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebasti\u00e1n, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javiera","family":"Soto","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebasti\u00e1n, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7453-7300","authenticated-orcid":false,"given":"Yennyfer","family":"Arancibia","sequence":"additional","affiliation":[{"name":"Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago 8320000, Chile; High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1110939, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"21850","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/S0140-6736(11)60993-8","article-title":"Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials","volume":"378","author":"Davies","year":"2011","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.prp.2015.01.004","article-title":"Tamoxifen resistance: from cell culture experiments towards novel biomarkers","volume":"211","author":"Nass","year":"2015","journal-title":"Pathol Res Pract"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02108-4","article-title":"Breast cancer: pathogenesis and treatments","volume":"10","author":"Xiong","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1186\/s12957-024-03553-9","article-title":"Understanding genetic variations associated with familial breast cancer","volume":"22","author":"Pal","year":"2024","journal-title":"World J Surg Oncol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1146\/annurev-med-070909-182917","article-title":"Mechanisms of endocrine resistance in breast cancer","volume":"62","author":"Osborne","year":"2011","journal-title":"Annu Rev Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1093\/jnci\/djac210","article-title":"Design and reporting of phase III oncology trials with prospective biomarker validation","volume":"115","author":"Liang","year":"2023","journal-title":"J Natl Cancer Inst"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17223720","article-title":"Bridging Discovery and Treatment: Cancer Biomarker","volume":"17","author":"Liu","year":"2025","journal-title":"Cancers (Basel)"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00781","article-title":"Estrogen Signaling in ER\u03b1-Negative Breast Cancer: ER\u03b2 and GPER","volume":"9","author":"Girgert","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.3390\/cells14221832","article-title":"Integrin \u03b1v\u03b23 as a Non-Genomic Estrogen Receptor in Breast Cancer for Signaling Pathways and Crosstalk","volume":"14","author":"Wang","year":"2025","journal-title":"Cells"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.steroids.2016.01.019","article-title":"Roles of the ER-\u03b136-EGFR\/HER2 positive regulatory loops in tamoxifen resistance","volume":"111","author":"Yin","year":"2016","journal-title":"Steroids"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/bcr938","article-title":"The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer","volume":"6","author":"Allred","year":"2004","journal-title":"Breast Cancer Res"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1210\/er.2011-1050","article-title":"Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses","volume":"33","author":"Vandenberg","year":"2012","journal-title":"Endocr Rev"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.reprotox.2012.12.001","article-title":"The effect of triclosan on the uterotrophic response to extended doses of ethinyl estradiol in the weanling rat","volume":"36","author":"Louis","year":"2013","journal-title":"Reprod Toxicol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.toxlet.2010.09.008","article-title":"Loss of BRCA1 leads to an increased sensitivity to Bisphenol A","volume":"199","author":"Jones","year":"2010","journal-title":"Toxicol Lett"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52505-x","article-title":"Bisphenol S and Bisphenol A disrupt morphogenesis of MCF-12A human mammary epithelial cells","volume":"9","author":"Atlas","year":"2019","journal-title":"Sci Rep"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Molina L, Figueroa CD, Ehrenfeld P. 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