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Activation of the Met tyrosine kinase growth factor receptor by its ligand HGF/SF has been shown to increase in vitro invasiveness in epithelial cell lines. To study the eect of Met-HGF/SF signaling in breast cancer cells, we transfected met, hgf/sf and dominant negative (DN) forms of met into the poorly dierentiated metastatic murine mammary adenocarcinoma cell line DA3. These cells express moderate levels of endogenous Met, which is rapidly phosphorylated in response to HGF/SF treatment. Met+hgf/sf transfection results in signi®cantly increased tumorigenic and metastatic activity in vivo accompanied by reduced tubule formation. DA3 cells transfected with DN forms of Met (DN-DA3) exhibit reduced Met phosphorylation following exposure to HGF/SF. Furthermore, as compared to the parental cells, the DN-DA3 cells exhibit diminished in vitro scattering and invasiveness, while in vivo they display greatly reduced tumorigenicity and spontaneous metastasis. Tumors emanating from DN-DA3 cells injected to BALB/C mice are highly dierentiated and display extensive tubule formation. These results suggest that Met-HGF/SF signaling is a determining factor in the delicate balance between dierentiation/tubule formation and tumorigenicity-metastasis.

BACKGROUND Prostatic innervation may participate in its homeostasis and growth. α‐Adrenergic inhibition alleviates clinical symptoms in benign prostatic hyperplasia. However, the prostatic effect of adrenergic agonists has not been investigated. This study deals with the prostatic effect of subchronic sympathomimetic stimulation. METHODS Male rats received daily subcutaneous injections of the α‐adrenergic agonist phenylephrine, 1, 10, or 20 mg/kg per day, the β‐adrenergic agonist isoproterenol, 1, 2.5 or 5 mg/kg per day, or saline, for 30 days, and the prostates were removed for histopathological examination. RESULTS Phenylephrine induced atypical prostatic hyperplasia, characterized by piling‐up with papillary and cribriform patterns, and budding‐out of epithelial cells. It decreased prostatic secretions and total weight. Similar results were observed in orchidectomized rats receiving exogenous testosterone supplementation. Isoproterenol had no prostatic morphological effect. CONCLUSIONS These results raise the possibility that sympathetic stimuli play a role in normal and aberrant growth and differentiation of prostatic epithelium, and suggests neurostimulants‐treated animals as a model to study the etiology and development of prostatic hyperplasia. Prostate 34:214–221, 1998.© 1998 Wiley‐Liss, Inc.

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