{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T08:08:39Z","timestamp":1779178119341,"version":"3.51.4"},"reference-count":30,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nicolaus Copernicus University IDUB programme"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Breast cancer has emerged as the preeminent global health crisis in oncology, currently standing as the most frequently diagnosed malignancy among women worldwide. Establishing novel predictive biomarkers is paramount to truly personalize treatment approaches, minimize unnecessary toxicity, and significantly improve long-term outcomes for patients with breast cancer. Breast cancer transcriptomic datasets were retrieved from the Gene Expression Omnibus and processed through standardized normalization procedures. Mutation-driven regulation of SYTL4 expression, treatment response to trastuzumab, cancer hallmark enrichment, and survival associations were evaluated using established bioinformatic tools and enrichment analysis based on integrated cancer hallmark gene sets. Additionally, DNA methylation profiles were analyzed. Herein, it is shown that SYTL4 mRNA expression is significantly (p = 2.01 \u00d7 10\u22124) diminished in breast cancer bearing BRCA1 mutations, suggesting a mechanistic interplay between BRCA1-driven genomic instability and SYTL4-regulated signaling cascades. Kaplan\u2013Meier survival analysis demonstrated that elevated SYTL4 mRNA expression is significantly associated with improved overall survival in HER2-positive breast cancer patients (HR = 0.72; p = 0.034). Consistently, SYTL4 expression was significantly higher in patients who responded to trastuzumab therapy, supporting its potential as a biomarker of therapeutic response. Epigenetic analysis further revealed significant differential DNA methylation of SYTL4 between tumor and unaffected control tissues (p &lt; 2.2 \u00d7 10\u221216), with region-specific hypomethylation in tumor regulatory regions. KEGG pathway and cancer hallmark enrichment analyses indicated that genes with prominent methylation changes are involved in cytokine signaling, growth factor pathways, and extracellular matrix remodeling, with the strongest associations observed for hallmarks related to genome instability, replicative immortality, resisting cell death, and metabolic reprogramming. In summary, we present that the gene SYTL4 is a prospective biomarker for survival and trastuzumab treatment responsiveness. Our observations posit that SYTL4 expression may signify a biological milieu conducive to sustained HER2 reliance and amplified therapeutic vulnerability.<\/jats:p>","DOI":"10.3390\/ijms27104533","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:35:43Z","timestamp":1779176143000},"page":"4533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SYTL4 May Serve as a New Predictive Biomarker for Survival and Trastuzumab Treatment Responsiveness in HER2-Positive Breast Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3344-5060","authenticated-orcid":false,"given":"Pawel","family":"Kordowitzki","sequence":"first","affiliation":[{"name":"Department of Basic and Preclinical Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland"},{"name":"Institute of Advanced Studies, Nicolaus Copernicus University, 87-100 Torun, Poland"},{"name":"Department of Gynecology with Center for Oncological Surgery, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/s41591-025-03502-3","article-title":"Global patterns and trends in breast cancer incidence and mortality across 185 countries","volume":"31","author":"Kim","year":"2025","journal-title":"Nat. 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