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squamous cell carcinomas, and sarcomas that exhibited aneuploidy. However, it is still unknown why some
tissue efficiently develop tumors, where others do not. Perhaps this is due to the high levels of centrosome
amplification induced in these models, since high-level chromosome instability and aneuploidy affect the
fitness of tumor cells, since they die, or stop proliferating after a few cell cycles [140,141] .

Moreover, studies from the Pellman group demonstrated that centrosome amplification also plays a role
in tumor progression by promoting invasion . In this particular study, invasion was measured using a
[161]
3D culture model after inducing centrosome amplification in untransformed human mammary epithelial
MCF10A cells either by a genetic approach (through the overexpression of PLK4 in the cells by a doxycycline-
inducible system) or by a pharmacological approach (through the inhibition of cytokinesis by the addition of
1,4-Dichlorobenzene, DBC, which also resulted in tetraploidy) . The advantages of using such approaches
[161]
are that this model allows the visualization of invasive protrusions and breast glandular structure
formation, which cannot be achieved by conventional cell culture. The major findings were that centrosome
amplification induced invasion in breast cells through an increase in the activity of Rac1 that disrupted
cell to cell adhesions, and the invasion was independent of the induction of tetraploidy . Likewise, our
[161]
laboratory showed that rescuing back centrosome amplification in Her2 breast cancer cells downregulated
+
for E2F3 by overexpressing GFP-Nek2 induced invasive protrusions in 3D culture . The Aneja’s laboratory
[162]
also showed that induction of centrosome amplification by overexpression of Plk4 in MCF10A cells induced
higher migration that correlated with vimentin expression . Experiments done by Denu expressing Plk4
[153]
in non-transformed MCF10A mammary epithelial cells demonstrated that acute acquisition of centrosome
amplification resulted in de-differentiation of cells, where CD24 levels were reduced, and CD44 increased,
suggesting that these cells were acquiring stem-cell features .
[13]
While the role of centrosome amplification in cancer is more clearly defined, the role of structural aberrations
has been unclear until recently. Structural centrosome aberrations are defined as changes in size and
composition of the pericentriolar matrix without changes in the number of centrioles . Overexpression
[163]
of Ninein-like protein (Nlp), a protein that is involved in microtubule nucleation causes structural
[164]
centrosome aberrations leading to spontaneous tumors in mice, including breast, ovary, and testicle . The
[165]
latest result from the Zhan laboratory is highly relevant to human disease since Nlp is overexpressed in breast,
lung, ovarian, and squamous head and neck cancers [165-167] . Interestingly, structural centrosome aberrations
lead to similar phenotypes as centrosome amplification, albeit by a non-cell autonomous mechanism, since
overexpression of Nlp contributes to invasion by causing stiffness in epithelial cells that culminate in budding
out of the acinar structures mitotic cells that do not contain centrosome aberrations .
[168]
Together, these experiments suggest that centrosome amplification and structural aberrations can contribute
to aggressive features of tumors by inducing invasion, increased grade/stage, and more stem-like features
of cells. The studies above suggest that the effects of centrosome amplification in tumor cells appear to be
context dependent.

MECHANISMS DRIVING CENTROSOME AMPLIFICATION AND CHROMOSOME INSTABILITY
The Vande Woude group first identified the mechanism by which centrosome amplification is generated in
tumors by showing that mouse embryonic fibroblasts lacking p53 displayed centrosome amplification . Later
[169]
on, other groups demonstrated that centrosome amplification was triggered by the loss of tumor suppressors
that include APC , BRCA1 , and BRCA2 . Regarding the mechanism, in p53-null mouse embryonic
[170]
[24]
[171]
fibroblasts, silencing or genetic ablation of Cdk2 and Cdk4 suppressed centrosome amplification . Also,
[104]
centrosome amplification in Brca1- or GADD45- deficient cells was associated with the downregulation of
Nek2 . Several studies revealed oncogenes could also drive centrosome amplification. For example, v-RAS
[172]
drives centrosome amplification through the MAPK pathway [26,173] . Further, H-Ras G12V and H-Ras G12V , and
c-Myc drive centrosome amplification through cyclin D1, Cdk4, and Nek2 in the non-transformed mammary