Epithelial ovarian carcinomas arise in a simple mesothelium (ovarian surface epithelium, OSE) but exhibit properties of oviductal and endometrial epithelia. Thus, during malignant progression, their differentiation proceeds from simple to complex, in contrast to carcinomas in other tissues. Related changes in OSE of women with a history of familial ovarian cancer indicate that this aberrant differentiation is initiated very early in neoplastic progression. The mechanisms underlying this process are not understood. Because cadherins are known regulators of differentiation, we investigated the relationship of the cadherins E, N and P to OSE morphology, growth patterns and differentiation in cultures of normal and metaplastic OSE from women with (FH-OSE) and without (NFH-OSE) a family history of ovarian cancer and in the ovarian carcinoma lines OVCAR-3 and CaOV3. We used immunofluorescence, RT-PCR, in situ hybridization and Western blotting. Our results define N-cadherin as the constitutively expressed cadherin of normal and metaplastic OSE and indicate that P-cadherin is undetectable while E-cadherin expression is conditional and related to genotype, stage of neoplastic progression and growth pattern. The altered expression of E-cadherin in apparently normal OSE of women with hereditary ovarian cancer syndromes in conjunction with the known capacity of E-cadherin to induce epithelial characteristics implicates this adhesion molecule as a possible inducer of the aberrant Mullerian differentiation which characterizes epithelial ovarian carcinomas. Abnormal differentiation in such (pre)-neoplastic tissues may represent an early, irreversible, non-mutational step in ovarian epithelial neoplastic progression.