INCREASED EXPRESSION OF SPECIFIC PROTEIN-TYROSINE PHOSPHATASES IN HUMAN BREAST EPITHELIAL-CELLS NEOPLASTICALLY TRANSFORMED BY THE NEU ONCOGENE

Protein tyrosine phosphorylation/dephosphorylation is a fundamental me chanism in the regulation of cell proliferation and neoplastic transfo rmation; this metabolic process is modulated by the opposing activitie s of protein tyrosine kinases and protein tyrosine phosphatases (PTPas es). While the role of protein tyrosine kinases has been examined exte nsively in human breast tumorigenesis, the role of PTPases in this pro cess is virtually unknown. To address this issue. an activated neu onc ogene was introduced into an immortalized nontumorigenic human breast epithelial cell line (184B5). This resulted in a substantial increase in P185neu expression, which led to the formation of progressively gro wing carcinomas after such cells were inoculated into athymic nude mic e. Importantly, a striking increase in the expression of specific PTPa ses, LAR and PTP1B, was observed in 3 independently neu transformed ce ll lines and their derived tumors. This elevation was verified at both the mRNA and protein levels. TC-PTP PTPase expression was only slight ly increased in these neu transformed cells, and no expression of CD45 PTPase was observed. The level of neu expression, as well as the diff erential expression between P185neu and LAR/PTP1B, directly correlated with tumorigenicity. Furthermore, rat mammary carcinomas with elevate d neu expression (neu-induced) also had sharply elevated LAR-PTPase ex pression when compared to rat mammary carcinomas with little or no neu expression (7,12-dimethylbenzanthracene induced); the level of expres sion of LAR PTPase was directly correlated with the level of neu expre ssion. Thus, our results provide the first evidence that, in human bre ast carcinoma cells and in rat mammary carcinomas that have an induced increase in neu expression, a consistent and substantial increase in the expression of specific PTPases occurs. The relationship between P1 85neu-protein tyrosine kinase expression and specific PTPase expressio n may play a critical role in human breast tumorigenesis.