Hypermethylation of 14-3-3 σ (stratifin) is an early event in breast cancer

• Published in: Oncogene Vol. 20; no. 26; pp. 3348 - 3353
• Main Authors: UMBRICHT, Christopher B, EVRON, Ella, GABRIELSON, Edward, FERGUSON, Anne, MARKS, Jeffrey, SUKUMAR, Saraswati
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 07.06.2001; Nature Publishing Group
• Subjects: 14-3-3 protein; 14-3-3 Proteins; 14-3-3-^s gene; Biological and medical sciences; Biomarkers, Tumor; Breast - metabolism; Breast - pathology; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Intraductal, Noninfiltrating - genetics; Carcinoma, Intraductal, Noninfiltrating - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; CpG Islands; Disease Progression; DNA - blood; DNA - genetics; DNA Methylation; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Epithelial Cells - metabolism; Epithelium; Exonucleases; Exoribonucleases; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Silencing; Humans; hypermethylation; Hyperplasia; Invasiveness; Leukocytes - metabolism; Molecular and cellular biology; Neoplasm Invasiveness - genetics; Neoplasm Proteins - genetics; Polymerase Chain Reaction; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Proteins - genetics; Sampling; Stratifin; Stromal Cells - metabolism; Tumorigenesis; Human; Mammary gland diseases; Gene silencing; Gene; Tumor progression; Tumor; Mammary gland; Gene expression; Methylation; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1204438

We have identified 14-3-3 sigma (sigma) as a gene whose expression is lost in breast carcinomas, primarily by methylation-mediated silencing. In this report, we investigated the timing of loss of sigma gene expression during breast tumorigenesis in vivo. We analysed the methylation status of sigma in breast cancer precursor lesions using microdissection for selective tissue sampling. We found hypermethylation of sigma in 24 of 25 carcinomas (96%), 15 of 18 (83%) of ductal carcinoma in situ, and three of eight (38%) of atypical hyperplasias. None of the five hyperplasias without atypia showed sigma-hypermethylation. Unexpectedly, patients with breast cancer showed sigma hypermethylation in adjacent histologically normal breast epithelium, while this was never observed in individuals without evidence of breast cancer. Also, samples of periductal stromal breast tissue were consistently hypermethylated, underscoring the importance of selective tissue sampling for accurate assessment of 14-3-3-sigma methylation in breast epithelium. These results suggest that hypermethylation of 14-3-3-sigma occurs at an early stage in the progression to invasive breast cancer, and may occur in apparently normal epithelium adjacent to breast cancer. These results provide evidence that loss of expression of sigma is an early event in neoplastic transformation.