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

We have identified 14-3-3 σ (σ) 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 σ gene expression during breast tumorigenesis in vivo. We analysed the methylation status of σ in breast cancer precursor lesions using microdissection for selective tissue sampling. We found hypermethylation of σ 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 σ-hypermethylation. Unexpectedly, patients with breast cancer showed σ 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-σ methylation in breast epithelium. These results suggest that hypermethylation of 14-3-3-σ 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 σ is an early event in neoplastic transformation.