Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast

Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q2 3.3, cause Cowden syndrome (CS), which is characterized by a high risk of b reast and thyroid cancers. Loss of heterozygosity of 10q22-24 markers and s omatic PTEN mutations have been found to a greater or lesser extent in a va riety of sporadic component and noncomponent cancers of CS, Among several s eries of sporadic breast carcinomas, the frequency of loss of flanking mark ers around PTEN is approximately 30 to 40%, and the somatic intragenic PTEN mutation frequency is <5%, In this study, we analyzed PTEN expression in 3 3 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammar y tissue had a distinctive pattern of expression: myoepithelial cells unifo rmly showed strong PTEN expression. The PTEN protein level in mammary epith elial cells was variable. Ductal hyperplasia with and without atypia exhibi ted higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples, 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN -positive tumors as well as in normal epithelium, the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immun ostain negative group, all had hemizygous PTEN deletion but no structural a lteration of the remaining allele. Thus, in these cases, an epigenetic phen omenon such as hypermethylation, decreased protein synthesis or increased p rotein degradation may be involved. In the cases with reduced staining, 5 o f 6 had hemizygous PTEN deletion and 1 did not have any structural abnormal ity. Finally, clinicopathological features were analyzed against PTEN prote in expression. Three of the 5 PTEN immunostain-negative carcinomas were als o both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study.