The role of the APC tumor suppressor in chromosomal instability

Genome Dynamics
Paola Alberici, Riccardo Fodde

Abstract

Colorectal cancer (CRC) still represents the model of choice to study the mechanisms underlying tumor initiation and progression. Accordingly, CRC has been central in the analysis of the role played by chromosomal instability (CIN) in tumor initiation and progression. Although loss of APC tumor suppressor function initiates the adenoma-carcinoma sequence in the vast majority of CRCs through constitutive activation of Wnt/beta-catenin signaling, the APC gene also represents a candidate CIN gene in CRC. Accordingly, two studies published in 2001 showed that truncating Apc mutations can lead to both quantitative and qualitative ploidy changes in primary mouse cell lines, mainly due to kinetochore and centrosome abnormalities. Here, we review and discuss the more recent literature on APC's functional activities possibly related to its role in eliciting CIN in tumor initiation and progression. We propose a model where loss and/or truncation of APC cause mitotic spindle defects that, upon somatic inactivation of other putative CIN genes (e.g. spindle and cell cycle checkpoint genes, DNA repair, telomere maintenance, etc.) underlie aneuploidy as observed in the majority of CRCs.

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