Loss of responsiveness to transforming growth factor β induces malignant transformation of nontumorigenic rat prostate epithelial cells

Binwu Tang, Katherine De Castro, Helen E. Barnes, W. Tony Parks, La Monica Stewart, Erwin P. Böttinger, David Danielpour, Lalage M. Wakefield*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Transforming growth factor (TGF)-βs are multifunctional growth factors, the properties of which include the potent inhibition of epithelial cell growth. Expression patterns of TGF-βs and TGF-β receptors in the normal prostate indicate that these growth regulators play key roles in prostatic development and proliferative homeostasis. Importantly, TGF-β receptor levels are frequently diminished in malignant human prostate tissue. To test the hypothesis that loss of TGF-β responsiveness is causally involved in the tumorigenic process, we have used retroviral transduction to introduce a dominant-negative mutant type II TGF-β receptor (DNR) into the premalignant rat prostatic epithelial cell line, NRP-152. High-level expression of the DNR abolished the ability of TGF-β 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-β receptor is an important tumor suppressor in the prostate, and furthermore, that loss of TGF-β responsiveness can contribute early in the tumorigenic process by causing the malignant transformation of preneoplastic cells.

Original languageEnglish (US)
Pages (from-to)4834-4842
Number of pages9
JournalCancer Research
Volume59
Issue number19
StatePublished - Oct 1 1999

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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