UP-REGULATION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR EXPRESSION BY THE HER2 NEU PROTOONCOGENE/

The HER2/neu (c-erbB2) protooncogene, which encodes a transmembrane re ceptor (p185(neu)), contributes to tumor cell invasion/metastasis thro ugh mechanism(s) which are, at present, poorly defined. Since basement membrane degradation is a prerequisite for tumor progression, we unde rtook a study to determine if the expression of urokinase, a key prote ase implicated in extracellular matrix proteolysis, was regulated by t his oncogene. Stable overexpression of a cDNA encoding HER2/neu in H46 0 lung cancer cells led to elevated secretion of urokinase which was a consequence of a higher level of protease mRNA. Transfection of the H ER2/neu-overexpressing B 104-1 cells with a CAT reporter construct dri ven by the urokinase promoter, gave rise to increased CAT activity whe n compared with parental NIH3T3 cells, which have low levels of HER2/n eu suggesting that the protooncogene can enhance urokinase promoter ac tivity. Since the enhanced expression of HER2/neu results in increased tumor invasiont/metastasis (1), these data suggest that, at least in vitro, HER2/neu-induced expression of urokinase may contribute to tumo r progression in p185(neu)-positive cancers.