Page 57 - Read Online

Page 10 of 20 Jusino et al. J Cancer Metastasis Treat 2018;4:43 I http://dx.doi.org/10.20517/2394-4722.2018.24

+
epithelial cells MCF10A . Likewise, Her2 breast cancer cells require Cdk4 and Nek2 to signal centrosome
[25]
amplification and chromosome instability . Further, the inhibition of Cdk2 suppressed Aurora A-induced
[174]
centrosome amplification in MCF7 breast cancer cells with inactive p53 by preventing the localization of
Aurora kinase A to centrosomes . However, not all oncogenes induce centrosome amplification as means
[175]
to initiate tumors, despite the induction of proliferation and apoptosis in pre-malignant mammary epithelial
lesions by c-Myc; the pre-malignant lesions were devoid of centrosome amplification . Nevertheless, c-Myc
[25]
eventually induced centrosome amplification in mammary tumors, suggesting that c-Myc requires other
genetic or epigenetic alterations to induce this abnormal process in mammary tumors.

There has been vast evidence demonstrating the essential role of the RB/E2F pathway in cell cycle regulation
and centrosome duplication, a pathway that is unregulated by oncogenes such as Ras and Myc . For
[176]
example, acute loss of Rb causes centrosome amplification . Although the E2F transcriptional factors have
[177]
redundant functions, each member of the family also has unique functions . Take for example E2F3,
[178]
whose loss in mouse embryonic fibroblasts results in unregulated cyclin E-dependent kinase activity, defects
in nucleophosmin B association with centrosomes, and premature centriole separation and duplication that
result in centrosome amplification, mitotic spindle defects, and aneuploidy . On the other hand, genetic
[109]
ablation of E2F1, E2F2, E2F4 or E2F5 does not cause centrosome amplification. Also, silencing E2F1 or E2F3
in Her2 breast cancer cells suppresses centrosome amplification, while overexpression of E2F1, E2F2, or
+
E2F3a in MCF10A cells is sufficient to trigger centrosome amplification and chromosome instability .
[110]
Chromosome instability is a broad term that refers to chromosome segregation errors, which results in
chromosome losses or rearrangements. As reviewed elsewhere, chromosome instability can occur as a
consequence of mitotic checkpoint defects, aberrations in centrosome duplication cycle, altered kinetochore
function, microtubule attachment defects, chromosome cohesion defects, and mutations causing or allowing
[17]
genomic instability . Although it has been shown that centrosome amplification leads to chromosome
instability , a recent study from Kuznetsova et al. showed that chromosome instability, tolerance of
[179]
[101]
mitotic errors, and multidrug resistance can be promoted by tetraploidization in human cells without
centrosome amplification. This study demonstrated that chromosome instability was tolerated by mutations
in p53 and the downregulation of the pro-apoptotic factors iASPP and cIAP2. Even though it remains a
question whether centrosome amplification is a cause or an effect of chromosome instability, both have
been shown to occur exclusively in malignant tumors that display aneuploidy and are associated with
[138]
tumor recurrence , metastasis [181,182] , and drug resistance [18,183,184] . Aneuploidy is defined by gains or losses of
[180]
whole chromosomes that play a role in tumor initiation, maintenance, and progression . Aneuploidy, as a
[138]
consequence of chromosomal instability, along with genomic instability (defects in DNA damage detection
and repair) lead to intra-tumor heterogeneity.

Chromosome instability occurs exclusively in malignant tumors that display aneuploidy; chromosome
instability affects tumor progression by generating intra-tumor heterogeneity [181,182] . For example,
chromosome instability has been shown to maintain intra-tumor heterogeneity in glioma cells . A more
[185]
recent study showed that chromosome missegregation drives intra-tumor heterogeneity in glioma cells;
cells with double minute chromosomes were more radio-resistant than those without them . Upon
[186]
irradiation, the double minute chromosomes allowed glioma cells to invade and become angiogenic. Thus, in
that setting, intra-tumor heterogeneity generated by the loss and gains of double minute chromosomes may
hinder cancer treatment by increasing cell invasiveness and radio-resistant cells. Several studies have shown
that chromosome instability also contributes to chemotherapy resistance [18,183,184,187] , making chromosome
instability a good therapeutic target. However, it is noteworthy that there is a complex relationship between
chromosome instability and therapeutic response that depends not only on the chromosome instability level,
but also in the genetic context and tissue type . As an example, a study conducted by Heerema et al.
[188]
[188]