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. 2002 Feb 19;99(4):1978-83.
doi: 10.1073/pnas.032479999. Epub 2002 Feb 5.

Centrosome amplification drives chromosomal instability in breast tumor development

Wilma L Lingle  1 , Susan L Barrett, Vivian C Negron, Antonino B D'Assoro, Kelly Boeneman, Wanguo Liu, Clark M Whitehead, Carol Reynolds, Jeffrey L Salisbury
Affiliations

Centrosome amplification drives chromosomal instability in breast tumor development

Wilma L Lingle et al. Proc Natl Acad Sci U S A. .

Abstract

Earlier studies of invasive breast tumors have shown that 60-80% are aneuploid and approximately 80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.

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Figures

Figure 1
Figure 1
FISH analysis. Flow chart of human breast tissue and tumor classification used in this study based on FISH analysis for chromosomes 3, 7, and 17. (Inset) FISH signals from two representative tumor nuclei: red signal, chromosome 3; green signal, chromosome 7; blue signal, chromosome 17.
Figure 2
Figure 2
Analysis of chromosomal instability, aneuploidy, and centrosome amplification for the five tissue ploidy groups. (A) Plot of CIN (% cells showing chromosome number differing from the modal value for that particular chromosome) for the various tissue ploidy groups. (B) Plots of aneuploidy and centrosome amplification. (Upper) Plot of chromosome losses and gains for each sample in each tissue ploidy group. For both A and B: red bars, chromosome 3; green bars, chromosome 7; blue bars, chromosome 17. (Lower) Plot of centrosome amplification for each sample in each tissue ploidy group. Yellow bars, normalized centrosome size and number index; maroon bars, normalized microtubule nucleation index. (C) Plots of three different measures of centrosome amplification (centrosome volume in μm3, centrosome number, and microtubule nucleation) for each tissue ploidy group. Bars in A and C indicate standard deviation.
Figure 3
Figure 3
Examples of immunofluorescence of centrosomes stained for centrin (green) in normal breast tissue (A) and centrosome amplification in breast tumors (B–E) and for microtubule nucleation (F–H) (green, anti-tubulin). (A) Region of a normal breast duct (lumen, center right) showing nuclei (red) located in the basal region of epithelial cells and pairs of centrioles (green, anti-centrin) located apically. (B–E) Examples of breast tumors showing the range of centrosome amplification in tumor tissue: (B) Diploid tumor. (C) Monosomy 17 tumor. (D) Stable aneuploid tumor. (E) Unstable aneuploid tumor. (F–H) Three examples of microtubule nucleation in touch preparations of breast tumor cells: (F) Diploid tumor. (G) Monosomy 17 tumor. (H) Stable aneuploid tumor.
Figure 4
Figure 4
(A) Analysis of centrosome amplification, CIN, Nottingham grade, and p53 mutations. Bar graph of centrosome amplification normalized against fibroblast centrosomes for individual DCIS, lymph node negative invasive ductal carcinoma (Ln-IDC), and lymph node positive invasive ductal carcinoma (Ln+IDC). Gray horizontal bar indicates average for five normal breast epithelial tissues including standard error. (B–D) Plots of CIN and centrosome amplification. CIN (%) for each tissue and each chromosome is plotted against centrosome number (B), centrosome volume (μm3) (C), and microtubule nucleation (D). Open symbols are values for normal breast tissue, gray-filled symbols are values for diploid tumors, and closed symbols are values for aneuploid tumor tissue. Red symbols, chromosome 3; green symbols, chromosome 7; blue symbols, chromosome 17. (E) Bar graph of microtubule nucleation for normal breast tissue (NB) and tumors of Nottingham grades G1, G2, and G3. (F) Bar graph of microtubule nucleation and p53 status (wild type, wt; mutant, mut) for normal breast tissue (NB), nonaneuploid (diploid + monosomy 17) tumors (NA), and aneuploid tumors (An). Bars in E and F indicate standard deviation.
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