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Loss of Responsiveness to Transforming Growth Factor ß Induces Malignant Transformation of Nontumorigenic Rat Prostate Epithelial Cells

Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-5055

Transforming growth factor (TGF)-ßs are multifunctional growth factors, the properties of which include the potent inhibition of epithelial cell growth. Expression patterns of TGF-ßs and TGF-ß receptors in the normal prostate indicate that these growth regulators play key roles in prostatic development and proliferative homeostasis. Importantly, TGF-ß receptor levels are frequently diminished in malignant human prostate tissue. To test the hypothesis that loss of TGF-ß responsiveness is causally involved in the tumorigenic process, we have used retroviral transduction to introduce a dominant-negative mutant type II TGF-ß receptor (DNR) into the premalignant rat prostatic epithelial cell line, NRP-152. High-level expression of the DNR abolished the ability of TGF-ß to inhibit cell growth, to promote cell differentiation, and to induce apoptosis, and it partially blocked the induction of extracellular matrix gene expression. When injected into nude mice, NRP-152-DNR cells formed carcinomas at 13 of 34 sites, compared with 0 of 30 sites for parental and control cells (P = 0.0001). We conclude that the type II TGF-ß receptor is an important tumor suppressor in the prostate, and furthermore, that loss of TGF-ß responsiveness can contribute early in the tumorigenic process by causing the malignant transformation of preneoplastic cells.

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