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Vol. 17, No. 4, pp. 488-501, February 15, 2003
1 Department of Cancer Biology, 2 Department of
Cell and Developmental Biology, 3 Department of Medicine,
4 Abramson Family Cancer Research Institute, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA; 5 Center for Comparative Medicine, University of
California, Davis, Davis, California 95616, USA
Aberrant activation of Wnt signaling is oncogenic and has been
implicated in a variety of human cancers. We have developed a
doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt
signaling. Using this model we show that targeted down-regulation of
the Wnt pathway results in the rapid disappearance of essentially all
Wnt-initiated invasive primary tumors as well as pulmonary metastases.
Tumor regression does not require p53 and occurs even in highly
aneuploid tumors. However, despite the dependence of primary mammary
tumors and metastases on continued Wnt signaling and the dispensability
of p53 for tumor regression, we find that a substantial fraction of
tumors progress to a Wnt-independent state and that p53 suppresses this
process. Specifically, loss of one p53 allele dramatically
facilitates the progression of mammary tumors to a
Wnt1-independent state both by impairing the regression of
primary tumors following doxycycline withdrawal and by promoting the
recurrence of fully regressed tumors in the absence of doxycycline.
Thus, although p53 itself is dispensable for tumor regression, it
nevertheless plays a critical role in the suppression of tumor
recurrence. Our findings demonstrate that although even advanced stages
of epithelial malignancy remain dependent upon continued Wnt signaling
for maintenance and growth, loss of p53 facilitates tumor escape and
the acquisition of oncogene independence.
[Keywords: Wnt; p53; mammary gland; inducible transgenic animals]
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