Zonula occludens-1 and HER-2/neu expression in invasive breast carcinoma

A subset of breast carcinomas shows unexplained overexpression of HER-2/neu protein without HER-2/neu gene amplification. These tumors are often scored 2+ by immunohistochemistry (DAKO HercepTest). In vitro, Zonula occludens-1 (ZO-1), a tight junction protein, can upregulate HER-2/neu expression by sequestering a repressor of the HER-2/neu gene promoter. To assess this relation in vivo, we examined the expression of ZO-1 in 2 series of breast carcinomas. In group 1, 35 invasive breast carcinomas previously scored by HercepTest for HER-2/neu status (negative [n = 12], 2+ [n = 13], 3+ [n = 10]) were examined by immunohistochemistry for expression of ZO-1. ZO-1 expression was then correlated with HER-2/neu expression status. Twenty-four of 35 carcinomas (69%) were positive for ZO-1 expression. Frequency of ZO-1 expression did not differ between HER-2/neu-negative carcinomas (67%) and 2+ positive carcinomas (77%). Carcinomas with 3+ HER-2/neu expression were less commonly positive for ZO-1 (60%), but this difference was not significant. Twenty tumors contained ductal carcinoma in situ (DCIS); 18 of 20 DCIS (90%) were positive for ZO-1. Interestingly, in those tumors with ZO-1-positive DCIS, 4 of 18 (22%) were negative for ZO-1 expression in the invasive tumor. In group 2, 31 of 42 (74%) fluorescent, in situ hybridization-nonamplified breast carcinomas showed ZO-1 expression, also with no significant difference in frequency between HER-2/neu-positive (by immunohistochemistry) and negative cases. ZO-1 expression does not correlate with HER-2/neu expression in breast carcinomas. Other causes of HER-2/neu protein overexpression should be sought in cases without HER-2/neu gene amplification.