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Centrosome Amplification and the Origin of Chromosomal Instability in Breast Cancer

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Centrosome Amplification and the Origin of Chromosomal Instability in Breast Cancer Centrosome Amplification and the Origin of Chromosomal Instability in Breast Cancer Jeffrey L. Salisbury Introduction Aneuploidy and chromosomal instability (CIN) are defming features of most aggressive breast cancers (BC). One consequence of CIN is a constantly changing genetic makeup of cancer cells - this in turn is a major driving force behind cancer cell heterogeneity, tumor progression, and acquisition of resistance to chemotherapeutics. How CIN arises in cancer and the mechanisms underlying this process have become a topical focus of cancer research. Yet it was nearly a century ago that Theodor Boveri first recognized that aneuploidy in cancer cells could arise through defects in the machinery for chromosomal segregation (1). Based on observations of abnormal chromosomal segregation in early sea urchin embryo development following dispermic fertilization and similarities to chromosomal anomalies seen in cancer, Boveri proposed that malignant tumors arise through centrosome defects that result in improper cell division (1). At about this same time, Galeotti came to a similar conclusion from his studies on tumors (2). Despite these compelling arguments and a strident call to the medical research community in JAM by Maynard Metcalf a decade later (3) imploring that "Boveri 's workshould be the startingpoint for a9studies of causes, inheritance or cure of cancer" it was not until near the end of the last century that investigations on human tumors and mouse models began to comborate Boveri's astute prescience (4-8). In this article, a review of centrosome structure and function, and the regulation of centrosome duplication in normal cells will be presented. Using recent studies on BC as an exemplary model, a discussion will follow on how deregulation of centrosome behavior can arise, result in centrosome amplification, and lead to CIN in cancer. Centrosome Structure and Behavior in Normal Cells The centrosome resides near the cell center (hence its name) and consists of a pair of centrioles and a surrounding matrix of pericentriolar material (PCM) that anchor microtubule nucleation sites and consequently determines the number and organiza- Centrosome Amplification and Breast Cancer 107 tion of microtubules in interphase cells. Like chromosomes, centrosomes double in number once in each cell cycle in a process that is initiated with centriole duplication. The centriole pair embodies an intrinsic counting mechanism that establishes the number of centrosome equivalents in the cell such that a pair of centrioles equals one, and two pair of centrioles equals two centrosome equivalents (9). Centrosomes increase in size through the recruitment of PCM and centrosomes of G2M cells show a dramatic increase in microtubule nucleating activity. At the time of cell division the two centrosomes (one residing at each spindle pole) organize microtubules of the bipolar mitotic spindle. In normal cells, spindle architecture is such that the two oppositely oriented half-spindle microtubule arrays (each arising from one of the two spindle poles) cast microtubules outward to engage and orient chromosomes so that sister chromatids face and can engage microtubules originating from opposite spindle poles. When all chromosomes are appropriately oriented and attached to microtubules originating from both spindle poles, the sister chromatids separate and move toward opposite poles by a molecular motor-driven process and dynamic shortening of their attached microtubules. Two new daughter cells form by cytokinesis and each inherit a complete complement of chromosomes along with one of the spindle poles that acts as the centrosome in the next cell cycle. Centrosome Amplification in Cancer Recent studies implicate centrosome abnormalities in the pathogenesis of cancer (4, 10-14). The term "centrosome amplification" refers to centrosomes that appear larger than normal, centrosomes that contain more than four centrioles, andlor when more than two centrosomes are present within a cell. In addition to these structural abnormalities, amplified centrosomes also show protein hyperphosphorylationand altered functional properties such as an increased microtubule nucleating capacity (4, 8, 15-17). Electron microscope studies revealed supernumerary centrioles in centrosomes of humans and animal model tumors, including leiomyosarcoma, neuroblastoma, glioma, and thymic carcinoid tumors (1 8-23). Systematic analyses of centrosomes in human breast carcinomas and a mouse model for prostate cancer revealed a range of abnormalities in centrosome structure including: excess number of centrioles, increased pericentriolar material, abnormal centriole orientation, and inverted polarity of centrosome location (5, 24). These structural centrosome abnormalities have been implicated as a potential cause of loss of cell and tissue architecture seen in cancer (i. e., anaplasia) through altered centrosome function in microtubule nucleation and organization, and to result in chromosome missegregation during mitosis as a consequence of multipolar spindle formation. 108 J.L. Salisbury Correlation of Centrosome Amplification, Aneuploidy, and Chromosomal Instability A key question is whether or not centrosome amplification leads to CIN and aneuploidy or is a consequence of them; the proverbial chicken and egg riddle. Aneuploidy is characterized as the state of an abnormal karyotype, having gains andlor losses of whole chromosomes. Aneuploidy occurs early in the development of many tumor types, suggesting that it may play a role in both tumorigenesis and tumor progression. Indeed, aneuploidy is present in the great majority of malignant tumors, in contrast to benign tumors, which are most often diploid. Aneuploidy can be distinguished from the persistent generation of chromosomal variations, termed "CIN", which reflects the rate of change in karyotype (25). Quantitative analysis of CIN can be determined as the percent of cells with a chromosome number different from the modal chromosome number. Thus, tumors may show either "stable aneuploidy" (low CIN) or "unstable aneuploidy." Unstable karyotypes may lead to phenotypic heterogeneity in cancer, reflecting the persistent generation of new chromosomal variations (26,27). The development of aneuploidy may be a consequence of centrosome amplification, which can lead to the formation of multipolar spindles and miss- segregate sister chromatids during mitosis, and as a result to high CIN. CIN occur exclusively in aneuploid tumors and tumor-derived cell lines in contrast to diploid tumors, which contain centrosomes that are functionally and structurallynormal (4, 26,28). The degree of genomic instability in aneuploid tumors parallels the degree of centrosome abnormalities in cell lines fiom breast (29), pancreas (1 3), prostate (30), colon (28), and cervix tumors (31), from short-term culture of mouse mammary tumors (32), and from SV40 ST over-expressing fibroblasts (33). When tissues were examined, centrosome abnormalitieswere higher in high-grade prostate tumors (30) and high-grade cervical tumors (31) than in low-grade tumors. In prostate cancer, centrosome amplification has been implicated in the development of abnormal mitoses and CIN facilitating progression to advanced stages of the disease (30, 34, 35). Strong support for a direct mechanistic link between centrosome amplification and CIN is suggested by the significant linear correlation between centrosome amplification and the rate of change in karyotype (CIN) seen in human breast tumors (26). Although such correlation alone does not necessarily imply cause and effect, these observations have led many authors to propose the hypothesis that centrosome amplification is the primary cause of genomic instability observed in most tumors (13, 26, 31, 33). As discussed above, Boveri first recognized these features of cancer cells nearly a century ago and proposed that centrosome defects could lead to mitotic and subsequent chromosomal abnormalities (1). An alternative hypothesis has been proposed that CIN seen in cancer cells is caused by aneuploidy, that is that aneuploidy itself destabilizes the karyotype and thus initiates CIN leading to widespread heterogeneity in tumor cell phenotypes (36-39). Centrosome Amplification and Breast Cancer 109 Several independent lines of evidence support the proposition that centrosome abnormalities drive genomic instability. In a recent study of human breast tumors, all specimens of ductal carcinoma in-situ examined showed significant centrosome amplification, while aneuploidy is present, on average, suggesting that centrosome amplification is an early event that occurs prior to invasion in breast tumors (26). Furthermore, cells transfected to express the HPV E7 oncoprotein undergo centrosome amplification prior to developing nuclear morphology associated with aneuploidy (40,41). Finally, in a xenograft model of pancreatic cancer, metastatic foci showed a higher incidence of centrosome amplification than did the primary xenograft, and abnormal centrosome numbers were accompanied by a higher frequency of abnormal mitoses (42). Taken together, these studies suggest that centrosome amplification may be an early event in turnorigenesis that can drive CIN and lead to genotypic and phenotypic diversity of cells within a tumor. Coordination of the DNA, Cell, and Centrosome Cycles in Normal Cells Because the fidelity of equal segregation of sister chromatids into daughter cells depends on the bipolar nature of the mitotic spindle it is essential that cells maintain
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