Bojana CRNOBRNJA, Toma? BÜDEFELD, Damjan GLAVA?, Gregor JEZERNIK, Sta?a JURGEC, Iztok TAKA?, Uro? POTO?NIK
Eurasian Journal of Medicine and Oncology - 2026;10(4):1-14
Introduction: GATA3 is a zinc-finger transcription factor essential for luminal cell fate specification in the mammary gland and a well-established marker of estrogen receptor (ER)-positive breast cancer (BC). High GATA3 expression characterizes the luminal A subtype and is associated with a favorable prognosis, while reduced expression and somatic mutations in its zinc-finger and C-terminal domains have been linked to aggressive tumor behavior. However, the molecular determinants of GATA3 loss in early-stage BC remain poorly understood. Objective: To characterize GATA3 mutational status in early-stage breast cancer patients. Methods: We characterized GATA3 protein expression by immunohistochemistry and assessed somatic mutations in exons 2-6 in a prospective cohort of 60 early-stage BC patients from Slovenia. We additionally performed a comprehensive analysis of somatic variations across the GATA3 gene using COSMIC data and evaluated the structural impact of single-nucleotide variants (SNVs) on GATA3 protein stability using in silico tools. Results: Most tumors (90%) exhibited high GATA3 immunoreactivity, which correlated significantly with ERalpha expression (p = 0.006). No somatic mutations were identified in exons 2-6 in tumors with absent or low GATA3 expression, suggesting that epigenetic mechanisms such as promoter hypermethylation drive expression loss in early-stage disease. Among 469 COSMIC-cataloged somatic variations, frameshift mutations predominated, and exon 6 harbored the highest mutational burden (55.88%). In silico analysis revealed that 51.46% of SNVs exerted destabilizing effects on GATA3 structure, predominantly within the zinc-finger 2 domain. Two variants, P42L and S93F, exhibited stabilizing effects warranting further functional investigation. Conclusion: Our findings provide characterization of GATA3 in early-stage BC from Slovenia and implicate epigenetic silencing as an alternative mechanism of GATA3 inactivation.
