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(American Journal of Pathology. 2002;161:1619-1634.)
© 2002 American Society for Investigative Pathology

Proliferation, but Not Apoptosis, Is Associated with Distinct ß-Catenin Expression Patterns in Non-Small-Cell Lung Carcinomas

Relationship with Adenomatous Polyposis Coli and G₁-to S-Phase Cell-Cycle Regulators

Athamassios Kotsinas^*, Konstantinos Evangelou^*, Panayotis Zacharatos^*, Christos Kittas^* and Vassilis G. Gorgoulis^*

From the Department of Histology-Embryology,^* Molecular Carcinogenesis Group, Medical School, University of Athens, Athens, Greece; and the Roy Castle International Institute for Lung Cancer Research, Liverpool, United Kingdom

ß-catenin (ß-cat) is a versatile component of homotypic cell adhesion and signaling. Its subcellular localization and cytoplasmic levels are tightly regulated by the adenomatous polyposis coli (APC) protein. Mutations in ß-cat (exon 3) or APC (MCR) result in ß-cat aberrant overexpression that is associated with its nuclear accumulation and improper gene activation. Data from experimental models have shown that ß-cat overexpression has a multitude of effects on cell-cycle behavior. In many of these aspects its function depends on major G₁ phase regulators. To the best of our knowledge, most of these issues have never been addressed concurrently in tumors. For this reason we investigated in a panel of 92 non-small-cell lung carcinomas, ß-cat and APC expression, and their relationship with cell-cycle kinetics (PI and AI) and ploidy status. Moreover, the above correlations were examined in relation to the main G₁/S-phase checkpoint regulators. Four ß-cat immunohistochemical expression patterns [membranous (11.1%), membranous-cytoplasmic (54.3%), cytoplasmic (9.9%), cytoplasmic-nuclear (24.7%)] and three APC immunohistochemical expression patterns [cytoplasmic (37.7%), cytoplasmic-nuclear (58%), nuclear (4.3%)] were observed, which were further confirmed by Western blot analysis on subcellular fractions in representative samples. The frequent presence of ß-cat in the cytoplasm is an indication of aberrant expression, whereas membranous and nuclear localization were inversely related. Absence of mutations in ß-cat (exon 3) and APC (MCR) suggest that ß-cat destruction mechanisms may be functional. However, expression analysis revealed attenuated levels for APC, indicating a residual ability to degrade ß-cat. Decreased levels were associated with loss of heterozygosity at the APC region in 24% of the cases suggesting that additional silencing mechanisms may be involved. Interestingly, the 90-kd APC isoform associated with apoptosis, was found to be the predominant isoform in normal and cancerous lung tissues. The most important finding in our study, was the correlation of nuclear ß-cat immunohistochemical localization with increased proliferation, overexpression of E2F1 and MDM2, aberrant p53, and low expression of p27^KIP, providing for the first time in vivo evidence that ß-cat-associated proliferation correlates with release of E2F1 activity and loss of p53- and p27^KIP-dependent cell-cycle checkpoints. Loss of these checkpoints is accompanied by low levels of APC, which possibly reflects a diminished ability to degrade ß-cat. Taken together our data indicate that cases with nuclear ß-cat immunohistochemical expression represent a subset of non-small-cell lung carcinomas that have gained an increased proliferation advantage in contrast to the other ß-cat immunohistochemical expression profiles.

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