{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:26Z","timestamp":1792790366035,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,22]]},"group-title":"Cell Biology","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Institute of General Medical Sciences","award":["1R16GM145545"],"award-info":[{"award-number":["1R16GM145545"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["U54 AA019765"],"award-info":[{"award-number":["U54 AA019765"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Minority Health and Health Disparities","award":["U54 MD012392"],"award-info":[{"award-number":["U54 MD012392"]}],"id":[{"id":"https:\/\/ror.org\/0493hgw16","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Alcohol consumption is an established risk factor for breast cancer, with a particularly strong association with estrogen receptor-positive (ER+) disease. Although the estrogenic activity of alcohol is well recognized, how alcohol-induced ER signaling is coupled to growth factor receptor pathways that promote tumor cell growth and progression remains incompletely understood. Here, we identify neuregulin-1 (NRG1) as a functional mediator, linking alcohol-induced ER activity to ErbB3 receptor tyrosine kinase signaling in ER+ breast cancer cells. Under estrogen-depleted conditions, alcohol induced proliferation, clonogenic growth, and S-phase progression in MCF-7 and T47D cells. Alcohol concurrently increased ER\u03b1 phosphorylation and transcriptional activity, including enhanced ER\u03b1 occupancy at the endogenous TFF1\/pS2 regulatory region, and activated ErbB3 and downstream Akt, ERK, and p38 signaling. Notably, alcohol induced NRG1 expression in both cell lines. Pharmacological inhibition of ER signaling with ICI 182,780 (fulvestrant) substantially attenuated NRG1 induction, ErbB3\/RTK activation, and alcohol-promoted growth, indicating that NRG1 induction and engagement of RTK signaling are strongly dependent on functional ER signaling. Conversely, shRNA-mediated NRG1 depletion suppressed alcohol-induced proliferation, clonogenic growth, and cell-cycle progression and markedly reduced alcohol-induced migratory and invasive phenotypes. NRG1 depletion also attenuated ErbB3\/Akt\/ERK signaling while reducing ER\u03b1 activation and ERE-dependent transcription, demonstrating a functional contribution of NRG1 to both arms of the signaling response. Together, these findings support a reciprocal ER-NRG1-ErbB3 signaling circuit in which alcohol-induced ER activity promotes NRG1 expression, while NRG1-dependent ErbB3 signaling reinforces ER activity and tumor-promoting phenotypes. Our study identifies NRG1 as a previously unrecognized molecular link between the estrogenic activity of alcohol and growth factor receptor signaling and provides a mechanistic framework for understanding alcohol-associated promotion of ER+ breast cancer.<\/jats:p>","DOI":"10.64898\/2026.09.21.753250","type":"posted-content","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:35:10Z","timestamp":1790116510000},"source":"Crossref","is-referenced-by-count":0,"title":["Alcohol Promotes ER+ Breast Cancer Cell Proliferation and Invasion Through the Upregulation of Neuregulin 1-Mediated ER-ErbB3 Crosstalk"],"prefix":"10.64898","author":[{"given":"Zhikun","family":"Ma","sequence":"first","affiliation":[{"name":"Julius L. Chambers Biomedical\/Biotechnology Research Institute; North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC, 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda B","family":"Parris","sequence":"additional","affiliation":[{"name":"Julius L. Chambers Biomedical\/Biotechnology Research Institute; North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC, 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohe","family":"Yang","sequence":"additional","affiliation":[{"name":"Julius L. 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Targeting of erbB3 receptor to overcome resistance in cancer treatment. 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