Amplified Centrosomes in Breast Cancer: A Potential Indicator of Tumor Aggressiveness

Abstract

Molecular mechanisms leading to genomic instability and phenotypic variation during tumor development and progression are poorly understood. Such instability represents a major problem in the management of breast cancer because of its contribution to more aggressive phenotypes as well as chemoresistance. In this study we analyzed breast carcinomas and tumor-derived cell lines to determine the relationship between centrosome amplification and established prognostic factors. Our results show that centrosome amplification can arise independent of ER or p53 status and is a common feature of aneuploid breast tumors. Centrosome amplification is associated with mitotic spindle abnormalities in breast carcinomas and thus may contribute to genomic instability and the development of more aggressive phenotypes during tumor progression.

Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

“…Therefore, we employed MCF-7 expressing recombinant green fluorescent protein (GFP)-centrin (MCF-7 GFPÀcetn2 ) to directly monitor the timing of centriole duplication (D'Assoro et al, 2001). MCF-7 GFPÀcetn2 and the parental MCF-7 cells showed similar proportions of G 1 , S and G 2 /M phase cells demonstrating that GFP-centrin expression had no gross effect on cell cycle progression (Figure 1a).…”

“…The human breast cancer cell line, MCF-7 (ATCC, Manassas, VA, USA), was modified to express a recombinant GFPcentrin2 chimera (MCF-7 GFPÀcetn2 ) and a temperature sensitive p53 construct mutated at residue 135 of valine (vMCF-7 DNp53 ) as described previously (Knippschild et al, 1996;D'Assoro et al, 2001D'Assoro et al, , 2004. For imaging of tumor localization and growth in living animals, cells were engineered to express a firefly luciferase protein (Hasegawa et al, 2006).…”

CDC25B Involvement in the Centrosome Duplication Cycle and in Microtubule Nucleation

“…Centrosome amplification may result either from uncontrolled centrosome duplication or from cytokinetic failure (3,4). The centrosome functions essentially to maintain cell polarity during interphase and ensure bipolar spindle assembly in mitosis (5,6), and the components required for these activities are primarily comprised of g-tubulin, which, in association with additional proteins, forms g-tubulin ring complexes (gTuRC) that act as templates for microtubule nucleation (5,7).…”

Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint

“…However, centrosome duplication is not strictly dependent on DNA replication since the centrosome and DNA cycles can be uncoupled (Balczon et al, 1995). In cancer, loss of coordination between the centrosome and DNA cycles may lead to centrosome amplification, increased frequency of multipolar mitoses, and chromosomal instability (Lingle et al, 1998(Lingle et al, , 2002Pihan et al, 2001;D'Assoro et al, 2002a). Tumor suppressors and cdk/cyclins play an important role in coordinating centrosome duplication with cell cycle events.…”