Ras levels and metalloproteinase activity in normal versus neoplastic rat mammary tissues.

We have previously reported that activated ras oncogenes can simultaneously switch on the metastatic phenotype and increased capability to degrade type IV collagen. Here the relationship between c-H-ras, metalloproteinase expression and metastatic behavior was studied in N-nitrosomethylurea (NMU)-induced rat mammary carcinomas, which are known to possess activated c-H-ras. When comparing normal rat breast tissue to mammary carcinomas there was no direct relationship between ras DNA levels and neoplastic changes. Furthermore, there were no consistent differences between metastatic and non-metastatic carcinomas, or between primary tumors and metastases. The NMU-induced rat mammary carcinomas expressed two major gelatinolytic metalloproteinases (gelatinases) of 65 and 92 kD, but only the 65 kD gelatinase was detected in normal breast tissue and a rat fibroma. Type IV collagenolytic activity per 5 micrograms of protein was two to three times higher in the mammary carcinomas than in the normal breasts, whereas the primary tumors did not differ from the corresponding metastases. This study shows that ras amplification is not necessary for development of the malignant or metastatic phenotype in the NMU-induced rat mammary carcinoma model. We have also found that induction of p21 ras protein synthesis in a v-H-ras transfected NIH/3T3 (433) cell line, containing a glucocorticoid promoter, does not lead to an increase in metastatic capacity.