{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:19Z","timestamp":1792790419344,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Cancer Biology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"American Cancer Society","award":["IRG-16-182-28"],"award-info":[{"award-number":["IRG-16-182-28"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health","award":["R21AG080176"],"award-info":[{"award-number":["R21AG080176"]}]},{"name":"National Institutes of Health","award":["R01CA207772"],"award-info":[{"award-number":["R01CA207772"]}]},{"name":"National Institutes of Health","award":["R01CA277946"],"award-info":[{"award-number":["R01CA277946"]}]},{"name":"National Institutes of Health","award":["R01CA274981"],"award-info":[{"award-number":["R01CA274981"]}]},{"name":"OSU Comprehensive Cancer Center","award":["Start-up funding"],"award-info":[{"award-number":["Start-up funding"]}],"id":[{"id":"https:\/\/ror.org\/028t46f04","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The hormone receptor-positive luminal subtype accounts for approximately 70% of all diagnosed breast cancer cases, with endocrine regimens serving as the first-line therapy. However, 30% to 50% of luminal breast cancer patients acquire therapeutic resistance with five to ten years of treatment. Understanding the mechanisms of endocrine resistance and identifying new therapeutic targets remain urgent priorities. Here, we demonstrate that expression of the alpha subunit of prolyl 4-hydroxylase (P4HA1), a key collagen-modifying enzyme, is significantly upregulated in endocrine therapy-resistant luminal breast cancer cells compared to parental endocrine therapy-sensitive cells. Clinically, elevated P4HA1 expression correlates with shortened relapse-free survival in patients with luminal breast cancer. Genetically knocking down P4HA1 or pharmacologically inhibiting its activity successfully restores the sensitivity of endocrine-resistant luminal breast cancer cells to hormone therapy. Mechanistically, we reveal that combining P4HA1 inactivation with endocrine treatment dramatically enhances endoplasmic reticulum (ER) stress-related gene expression. Consistently, treating resistant cells with an exogenous ER stress inducer similarly enhances sensitivity to hormone therapy. Furthermore, we demonstrate that ER stress induced by P4HA1 inactivation is molecularly mediated by an accumulation of reactive oxygen species (ROS). Together, these findings uncover a novel, non-canonical role for P4HA1 as a critical mediator linking endocrine resistance to cellular stress adaptations, positioning P4HA1 as a promising therapeutic vulnerability in endocrine-resistant breast cancer. P4HA1 serves as a necessary role in maintenance resistant state, making it a viable target for combination therapies to overcome endocrine resistance.<\/jats:p>","DOI":"10.64898\/2026.09.30.755755","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:25:12Z","timestamp":1790936712000},"source":"Crossref","is-referenced-by-count":0,"title":["P4HA1 sustains endocrine resistance in luminal breast cancer via regulation of cellular stress"],"prefix":"10.64898","author":[{"given":"Dalton","family":"Hironaka","sequence":"first","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"name":"Molecular, Cellular and Development Biology Program, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baorui","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"name":"OSU Nutrition Graduate Program, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"name":"James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"name":"James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Schiff","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Arkansas for Medical School, Little Rock, AR 72205, USA"},{"name":"Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaofeng","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"name":"James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA"},{"name":"Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"1","key":"2026100708201906000_2026.09.30.755755v1.1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1111\/j.1749-6632.1990.tb17925.x","article-title":": Molecular Biology of Prolyl 4-Hydroxylase","volume":"580","year":"1990","journal-title":"Annals of the New York Academy of Sciences"},{"key":"2026100708201906000_2026.09.30.755755v1.2","doi-asserted-by":"publisher","DOI":"10.3109\/10409231003627991"},{"key":"2026100708201906000_2026.09.30.755755v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.11.5989"},{"key":"2026100708201906000_2026.09.30.755755v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0945-053X(98)90009-9"},{"issue":"7","key":"2026100708201906000_2026.09.30.755755v1.5","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.3390\/cancers12071788","article-title":": Characterization of Glycolysis-Associated Molecules in the Tumor Microenvironment Revealed by Pan-Cancer Tissues and Lung Cancer Single Cell Data","volume":"12","year":"2020","journal-title":"Cancers (Basel"},{"key":"2026100708201906000_2026.09.30.755755v1.6","doi-asserted-by":"crossref","unstructured":"Zhao Q , Liu J : P4HA1, a Prognostic Biomarker that Correlates With Immune Infiltrates in Lung Adenocarcinoma and Pan-Cancer. 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