Chromosome segregation errors: a double-edged sword - TI Pharma

Introduction
Aneuploidy is a common genetic alteration in solid human cancers and refers to an abnormal
chromosome number 236 . The main underlying phenotype that causes aneuploidy is known as
chromosomal instability (CIN), which is the frequent gain and loss of whole chromosomes during
cell division 270,289 . The widespread occurrence of aneuploidy in cancers has led to the hypothesis
that CIN may contribute to tumor formation and/or progression 287 . In support of this, CIN occurs at
an early stage of colorectal tumorigenesis and has been shown to occur in cell cultures of colon,
prostate, oropharynx, lung and breast tumors 289,312,437-439 . Moreover, a strong correlation of CIN
with aggressiveness of the tumor, resistance to chemotherapeutics and poor patient prognosis has
been reported 271-273,275-280,283 , and a striking correlation was observed between a CIN signature and
different grades of primary breast cancers and derivative lung metastases 275 . Such observations have
spurred extensive investigations into the potential role of CIN in tumor formation and progression,
and several mouse models have resulted in important advances in our understanding of this 398 .
Errors in mitotic chromosome segregation are the predominant cause of CIN. Such errors are
normally prevented by the error-correction and mitotic checkpoint machineries. The mitotic
or spindle assembly checkpoint is a safeguarding mechanism that delays mitotic exit until
error-correction has ensured that all chromosomes are attached and aligned correctly on the
mitotic spindle 440 . The mitotic checkpoint is a robust signalling cascade that originates from the
chromosomal anchor points of mitotic spindle microtubules, termed kinetochores, whenever
these kinetochores are not interacting with microtubules 441 . The core conserved components of
the mitotic checkpoint are Mad1, Mad2, Bub3, BubR1, Bub1, and Mps1. Depletion or inactivation
of any one of these components abrogates mitotic checkpoint activity, resulting in chromosome
missegregations and thus aneuploidy 441 . On top of their role in the mitotic checkpoint, Mps1,
BubR1 and Bub1 have also been shown to be important players in error-correction 116,442,443 .
Although yet to be shown for human cancers, defects in both error correction and mitotic checkpoint
functioning have been hypothesized to cause CIN in tumor cells and experimental weakening of either
has supported this 290 . Additional defects that have been hypothesized to contribute to CIN are sister
chromatid cohesion defects, cytokinesis defects and centrosome overduplication 335,338,353,355,356,444 .
Various mouse models for chromosomal instability have been generated 392 . These mouse models mainly
target proteins which have a role in mitotic progression, such as CENP-E, UbcH10 and Cdc20 and the
mitotic checkpoint proteins Mad2, Mad1, Bub1, Bub3, BubR1, 332,392,400,413 . Homozygous deletion of all
studied mitotic checkpoint components causes early embryonic lethality 392 . The effects of heterozygous
deletion, however, depend on the gene and tissue examined. For instance, Mad2 +/- and Mad1 +/- mice
develop tumors at long latency 291,298 , while on the other hand, heterozygous deletion of Bub1, Bub3
or BubR1 did not lead to spontaneous tumor formation, despite development of aneuploidy 295-297,300 .
However, treating some of these models with carcinogens or crossing them with tumor prone mouse
models did increase the extent and speed of tumor formation 286,295,296,401 . In contrast to heterozygous
deletion, reducing levels of Bub1 using hypomorphic mice resulted in spontaneous tumorigenesis 395 ,
indicating that different levels of CIN may have different outcomes, depending on the genetic context.
In contrast to the tumor promoting roles of CIN, excessive CIN and aneuploidy are not tolerated at
the cellular level 292,445,446 . Indeed, CIN may also confer a tumor suppressive function in certain mouse
models 286,397 and more importantly, in human patients 404 . In line with this, enhancing chromosome
segregation errors through mitotic checkpoint inhibition has been suggested as a useful anti-cancer
strategy 292,299,447 .
The abovementioned studies suggest that the contribution of CIN to tumor formation or progression
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Cre-inducible Mps1 knock-in mouse model (CiMKi)
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