Abstract
Purpose
Centrosome aberration in number and/or size is reportedly often observed in human breast cancer. The aim of this study was to investigate the relationship between centrosome aberration and chromosomal instability as well as the expression of centrosome regulators such as BRCA1, Aurora-A, and p53.
Methods
Centrosome aberration in number and size was determined immunohistochemically using the anti-γ-tubulin antibody, and chromosomal instability was evaluated by fluorescence in situ hybridization analysis of chromosomes 1, 11, and 17 in paraffin sections from 50 human breast cancers. Immunohistochemical examination of BRCA1, Aurora-A, and p53 was also performed to examine the relationship of their expression with centrosome aberration.
Results
Percentage of tumor cells with centrosome aberration in size varied from 0.9 to 30.4% (median 9.5%) and in number it varied from 0.5 to 86.5% (median 34.5%) in each tumor. No significant association in number or size, however, was observed between chromosomal instability and centrosome aberration. Numerical centrosome aberration was significantly associated with negative BRCA1 expression (P = 0.001). Breast tumors (n = 3) from patients with a proven BRCA1 germline mutation also showed a significant relationship with numerical centrosome aberration (P = 0.011). On the other hand, expression of Aurora-A or p53 was not significantly associated with centrosome aberration in either number or size.
Conclusions
Centrosome aberration is not associated with chromosomal instability, indicating the importance of other mechanisms in the induction of chromosomal instability in human breast cancer. BRCA1, but not Aurora-A and p53, is significantly involved in the pathogenesis of centrosome aberration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Brinkley BR, Goepfert TM (1998) Supernumerary centrosomes and cancer: Boveri’s hypothesis resurrected. Cell Motil Cytoskeleton 41(4):281–288. doi:10.1002/(SICI)1097-0169(1998)41:4<281::AID-CM1>3.0.CO;2-C
Deng CX (2002) Roles of BRCA1 in centrosome duplication. Oncogene 21(40):6222–6227. doi:10.1038/sj.onc.1205713
Deng CX, Brodie SG (2000) Roles of BRCA1 and its interacting proteins. Bioessays 22(8):728–737. doi:10.1002/1521-1878(200008)22:8<728::AID-BIES6>3.0.CO;2-B
Duensing S, Lee BH, Dal Cin P, Munger K (2003) Excessive centrosome abnormalities without ongoing numerical chromosome instability in a Burkitt’s lymphoma. Mol Cancer 2:30. doi:10.1186/1476-4598-2-30
Dutertre S, Prigent C (2003) Aurora-A overexpression leads to override of the microtubule-kinetochore attachment checkpoint. Mol Interv 3(3):127–130. doi:10.1124/mi.3.3.127
Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF (1996) Abnormal centrosome amplification in the absence of p53. Science 271(5256):1744–1747. doi:10.1126/science.271.5256.1744
Ghadimi BM, Sackett DL, Difilippantonio MJ, Schrock E, Neumann T, Jauho A et al (2000) Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosomes Cancer 27(2):183–190. doi:10.1002/(SICI)1098-2264(200002)27:2<183::AID-GCC10>3.0.CO;2-P
Guo HQ, Gao M, Ma J, Xiao T, Zhao LL, Gao Y et al (2007) Analysis of the cellular centrosome in fine-needle aspirations of the breast. Breast Cancer Res 9(4):R48. doi:10.1186/bcr1752
Kellogg DR, Moritz M, Alberts BM (1994) The centrosome and cellular organization. Annu Rev Biochem 63:639–674. doi:10.1146/annurev.bi.63.070194.003231
Kronenwett U, Huwendiek S, Castro J, Ried T, Auer G (2005) Characterisation of breast fine-needle aspiration biopsies by centrosome aberrations and genomic instability. Br J Cancer 92(2):389–395. doi:10.1038/sj.bjc.6602246
Lacroix M, Toillon RA, Leclercq G (2006) p53 and breast cancer, an update. Endocr Relat Cancer 13(2):293–325. doi:10.1677/erc.1.01172
Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386(6625):623–627. doi:10.1038/386623a0
Lingle WL, Barrett SL, Negron VC, D’Assoro AB, Boeneman K, Liu W et al (2002) Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci USA 99(4):1978–1983. doi:10.1073/pnas.032479999
Meraldi P, Lukas J, Fry AM, Bartek J, Nigg EA (1999) Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat Cell Biol 1(2):88–93. doi:10.1038/10054
Miyoshi Y, Iwao K, Egawa C, Noguchi S (2001) Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int J Cancer 92(3):370–373. doi:10.1002/ijc.1200
Mussman JG, Horn HF, Carroll PE, Okuda M, Tarapore P, Donehower LA et al (2000) Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression. Oncogene 19(13):1635–1646. doi:10.1038/sj.onc.1203460
Orr-Weaver TL, Weinberg RA (1998) A checkpoint on the road to cancer. Nature 392(6673):223–224. doi:10.1038/32520
Parvin JD (2004) Overview of history and progress in BRCA1 research: the first BRCA1 decade. Cancer Biol Ther 3(6):505–508
Parvin JD, Sankaran S (2006) The BRCA1 E3 ubiquitin ligase controls centrosome dynamics. Cell Cycle 5(17):1946–1950
Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P et al (1998) Centrosome defects and genetic instability in malignant tumors. Cancer Res 58(17):3974–3985
Quintyne NJ, Reing JE, Hoffelder DR, Gollin SM, Saunders WS (2005) Spindle multipolarity is prevented by centrosomal clustering. Science 307(5706):127–129. doi:10.1126/science.1104905
Rose MD, Biggins S, Satterwhite LL (1993) Unravelling the tangled web at the microtubule-organizing center. Curr Opin Cell Biol 5(1):105–115. doi:10.1016/S0955-0674(05)80015-8
Salisbury JL, D’Assoro AB, Lingle WL (2004) Centrosome amplification and the origin of chromosomal instability in breast cancer. J Mammary Gland Biol Neoplasia 9(3):275–283. doi:10.1023/B:JOMG.0000048774.27697.30
Sankaran S, Parvin JD (2006) Centrosome function in normal and tumor cells. J Cell Biochem 99(5):1240–1250. doi:10.1002/jcb.21003
Schneeweiss A, Sinn HP, Ehemann V, Khbeis T, Neben K, Krause U et al (2003) Centrosomal aberrations in primary invasive breast cancer are associated with nodal status and hormone receptor expression. Int J Cancer 107(3):346–352. doi:10.1002/ijc.11408
Sibon OC, Kelkar A, Lemstra W, Theurkauf WE (2000) DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila embryos. Nat Cell Biol 2(2):90–95. doi:10.1038/35000041
Sluder G, Nordberg JJ (2004) The good, the bad and the ugly: the practical consequences of centrosome amplification. Curr Opin Cell Biol 16(1):49–54. doi:10.1016/j.ceb.2003.11.006
Starita LM, Machida Y, Sankaran S, Elias JE, Griffin K, Schlegel BP et al (2004) BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number. Mol Cell Biol 24(19):8457–8466. doi:10.1128/MCB.24.19.8457-8466.2004
Stearns T (2001) Centrosome duplication. a centriolar pas de deux. Cell 105(4):417–420. doi:10.1016/S0092-8674(01)00366-X
Takami S, Kawasome C, Kinoshita M, Koyama H, Noguchi S (2001) Chromosomal instability detected by fluorescence in situ hybridization in Japanese breast cancer patients. Clin Chim Acta 308(1/2):127–131. doi:10.1016/S0009-8981(01)00473-9
Tarapore P, Horn HF, Tokuyama Y, Fukasawa K (2001) Direct regulation of the centrosome duplication cycle by the p53-p21Waf1/Cip1 pathway. Oncogene 20(25):3173–3184. doi:10.1038/sj.onc.1204424
Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW et al (1999) Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3(3):389–395. doi:10.1016/S1097-2765(00)80466-9
Yang Q, Sakurai T, Mori I, Yoshimura G, Nakamura M, Nakamura Y et al (2001) Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas. Cancer 92(1):54–60. doi:10.1002/1097-0142(20010701)92:1<54::AID-CNCR1291>3.0.CO;2-8
Conflict of interest statement
There is no conflict of interest to declare in relation to this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shimomura, A., Miyoshi, Y., Taguchi, T. et al. Association of loss of BRCA1 expression with centrosome aberration in human breast cancer. J Cancer Res Clin Oncol 135, 421–430 (2009). https://doi.org/10.1007/s00432-008-0472-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-008-0472-5