Carcinogenesis, Vol 19, 195-205, Copyright © 1998 by Oxford University Press
MA Shibata, CL Jorcyk, DE Devor, K Yoshidome, S Rulong, J Resau, N Roche, AB Roberts, JM Ward and JE Green
We demonstrate that targeted expression of SV40 large T antigen (TAg) to
the urethral (periurethral) and bulbourethral gland epithelium leads to
adenocarcinoma formation in these tissues after 7 months of age, which are
extremely rare sites for spontaneous tumor formation in humans. The
development of proliferative lesions in the urethral gland predictably
follows a temporal course of progression with approximately one third of
male animals developing urethral tumors by 1 year of age. Tumor progression
in these organs correlates to the level of TAg and p53 expression.
Immunoprecipitation confirmed that SV40 TAg protein was bound to p53 and Rb
p110 in vivo. Expression of transforming growth factor beta (TGFbetas) was
evaluated during tumor progression of urethral gland carcinomas. Elevations
of intracellular and extracellular TGFbeta1 and extracellular TGFbeta3 were
found in preneoplastic and neoplastic lesions, suggesting that increased
TGFbetas may augment tumor growth. c-Met expression showed a tendency for
increased expression in the urethral gland carcinomas. We speculate that
the directed expression of SV40 TAg by the hormone responsive C3(1) gene
and subsequent tumor formation in these organs is influenced by androgens,
since these tissues and carcinomas express androgen receptor (AR) and arise
only in male transgenic mice. Several cell lines established from the
urethral carcinomas were also shown to express AR, but are not androgen
dependent in culture. To our knowledge, this is the first transgenic animal
model for urethral and bulbourethral carcinomas. This transgenic mouse
model and the cell lines derived from it may provide a unique opportunity
for dissecting molecular mechanisms involved in the tumorigenesis of these
organs which otherwise rarely develop cancer.
ARTICLES
Altered expression of transforming growth factor betas during urethral and bulbourethral gland tumor progression in transgenic mice carrying the androgen-responsive C3(1) 5' flanking region fused to SV40 large T antigen
Laboratory of Cellular Regulation and Carcinogenesis, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
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