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(American Journal of Pathology. 2004;164:1739-1749.)
© 2004 American Society for Investigative Pathology

ß-Catenin Simultaneously Induces Activation of the p53-p21WAF1 Pathway and Overexpression of Cyclin D1 during Squamous Differentiation of Endometrial Carcinoma Cells

Makoto Saegusa^*, Miki Hashimura^*, Takeshi Kuwata, Mieko Hamano and Isao Okayasu^*

From the Department of Pathology^* and Division of Cell and Tissue Culture, Kitasato University School of Medicine, Kanagawa; and the Department of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

The functional consequences of up-regulation of ß-catenin as a transcription factor are complex in different tumors. To clarify roles during squamous differentiation (SqD) of endometrial carcinoma (Em Ca) cells, we investigated expression of ß-catenin, as well as cyclin D1, p53, p21WAF1, and PML (promyelocytic leukemia) in 80 cases of Em Ca with SqD areas, in comparison with cell proliferation determined with reference to Ki-67 antigen positivity. The impact of ß-catenin-T-cell factor (TCF)-mediated transcription was also examined using Em Ca cells. In clinical cases, nuclear ß-catenin accumulation was more frequent in SqD areas, being positively linked with expression of cyclin D1, p53, and p21WAF1, and inversely with Ki-67 and PML immunoreactivity. Significant correlations of nuclear ß-catenin, cyclin D1, p53, and p21WAF1 were noted between SqD and the surrounding carcinoma lesions. The Ishikawa cell line, with stable or tetracycline-regulated expression of mutant ß-catenin, showed an increase in expression levels of cyclin D1, p14ARF, p53, and p21WAF1 but not PML, and activation of ß-catenin-TCF4-mediated transcription determined with TOP/FOP constructs. The cell morphology was senescence-like rather than squamoid in appearance. Moreover, overexpressed ß-catenin could activate transcription from p14ARF and cyclin D1 promoters, in a TCF4-dependent manner. These findings indicate that in Em Cas, nuclear ß-catenin can simultaneously induce activation of the p53-p21WAF1 pathway and overexpression of cyclin D1, leading to suppression of cell proliferation or induction of cell senescence. However, overexpression of ß-catenin alone is not sufficient for development of a squamoid phenotype in Em Ca cells, suggesting that nuclear accumulation is an initial signal for trans-differentiation.

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