Published in Cancer Detection and Prevention 1999; 23(4):297-308.

nm-23, c-Erbb-2, and Progesterone Receptor Expression in Invasive Breast Cancer: Correlation with Clinicopathologic Parameters

Lydia L. Nakopoulou, M.D.,a Dimitris Tsitsimelis, M.D.,a Andreas Ch. Lazaris, M.D.,a Anastasia Tzonou, M.D.,b Hara Gakiopoulou, M.D.,a Christina Ch. Dicoglou, M.D.,a and Panayiotis S. Davaris, M.D.a

Departments of a Pathology and b Hygiene and Epidemiology, University of Athens, Athens, Greece

Address all correspondence and reprint requests to: Lydia Nakopoulou, M.D., Department of Pathology, University of Athens Medical School, 75 Mikras Assias Str., Goudi, GR-115 27 Athens, Greece.

ABSTRACT: Downregulation of nm-23 antimetastasis gene has been associated with disease progression in some human tumors. NPD kinase A is the product of the H1 isotype of the nm23 gene and its value as a marker of metastatic potential is well worth investigating. The expression of the nm23-HJ gene peptide was immunohistochemically evaluated in 191 primary mammary cancer tissues. A three-step immunoperoxidase staining procedure was performed and any association of our results with several classical clinicopathologic indicators, including hormonal status and c-erbB-2 oncoprotein membrane immunoexpression, was examined. NDP kinase A-positive cytoplasmic immunolabeling was noticed in 64% of all specimens123/191 which frequently demonstrated positive progesterone receptor (PgR) status (p = 0.001) and were furthermore characterized by high PgR immunoreactivity rates. This association was significant by both univariate and multivariate statistical analysis. The double nm23-HI(+)/PgR(+) phenotype was more frequently detected than any other combined phenotype of these markers. The nm23-HI gene peptide was generally detected in a remarkable proportion of malignant cells, either in the invasive or the intraductal tumor components. Notably, large-cell ductal carcinomas in situ were characterized by lower nm23-HI immunoreactivity rates when compared with other in situ cancer types. Quantitatively increased nm23-HI immunopositive staining was more frequently observed in special histologic types of infiltrating cancers, in high nuclear grade tumors, as well as in carcinomas with high PgR levels (p = 0.05). The nm23-HI(-)/c-erbB-2(+) phenotype was more often detected in the cancers of this study than the nm23-HI(+)/c-erbB-2(+) one. The former phenotype was correlated to postmenopausal ages as well as to extensive axillary nodal involvement by univariate statistical analysis. It is noteworthy that nm23-HI(-) status, on its own, was not statistically associated either with the presence or with a high number of involved lymph nodes. On the contrary, nm23-HI immunopositivity was, paradoxically, more frequently observed in tumors of relatively increased TN tumor stage. Tumor progression is thus more likely to depend on the c-erbB-2 gene’s overexpression. Possibly, any favorable outcome in nm23-HI(+) cases might be due to the fact that they also express PgR, which is a marker of a more functionally differentiated phenotype.

KEY WORDS: breast cancer, c-erbB-2 oncoprotein, immunohistochemistry, metastasis, nm23-HI protein, progesterone receptor protein.