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

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 i n breast cancer precursor lesions using microdissection for selective tissu e 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 a typical hyperplasias. None of the five hyperplasias without atypia showed s igma -hypermethylation. Unexpectedly, patients with breast cancer showed si gma hypermethylation in adjacent histologically normal breast epithelium, w hile this was never observed in individuals without evidence of breast canc er. Also, samples of periductal stromal breast tissue were consistently hyp ermethylated, 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 s tage in the progression to invasive breast cancer, and may occur in apparen tly normal epithelium adjacent to breast cancer. These results provide evid ence that loss of expression of sigma is an early event in neoplastic trans formation.