Aurora-A amplification associated with BRCA2 mutation in breast tumours

Bödvarsdóttir, Sigrídur K.; Hilmarsdóttir, Hólmfríður; Birgisdottir, Valgerdur; Steinarsdóttir, Margrét; Jonasson, Jón G.; Eyfjörd, Jórunn E.

doi:10.1016/j.canlet.2006.06.003

Cited by 28 publications

(25 citation statements)

References 35 publications

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“…Basal-like breast tumors account for approximately 10-15% of all breast cancers, characteristically express high-molecular weight basal cytokeratins and are considered as clinically aggressive tumors (23). Amplification at 20q is a common chromosomal change in hereditary BRCA1 and BRCA2 breast and ovarian cancers (24,25) and AURKA gene amplification has been associated with breast tumors harbouring a BRCA2 mutation (26). These hereditary tumors, especially those in BRCA1 mutation carriers, are generally considered to belong to a basal-like subtype of breast cancer (17).…”

Section: Discussionmentioning

confidence: 99%

Aurora-A gene is frequently amplified in basal-like breast cancer

Staff

Isola²,

Jumppanen³

et al. 2009

Oncol Rep

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Section: Discussionmentioning

confidence: 99%

Aurora-A gene is frequently amplified in basal-like breast cancer

Staff

Isola²,

Jumppanen³

et al. 2009

Oncol Rep

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“…One study demonstrated increased risk of invasive breast cancer in postmenopausal women with a genotype Ile31 and Val52, another known aurora A SNP [Cox et al, 2006]. Finally aurora A amplification was more common in breast tumors carrying the BRCA2 999del5 mutation [Bodvarsdottir et al, 2007].…”

Section: Aurora a And Cancermentioning

confidence: 97%

Aurora A, centrosome structure, and the centrosome cycle

Lukasiewicz

Lingle

2009

Environ and Mol Mutagen

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The centrosome, also known as the microtubule organizing center of the cell, is a membrane-less organelle composed of a pair of barrel-shaped centrioles surrounded by electron-dense pericentriolar material. The centrosome progresses through the centrosome cycle in step with the cell cycle such that centrosomes are duplicated in time to serve as the spindle poles during mitosis and that each resultant daughter cell contains a single centrosome. Regulation of the centrosome cycle with relation to the cell cycle is an essential process to maintain the ratio of one centrosome per new daughter cell. Numerous mitosis-specific kinases have been implicated in this regulation, and phosphorlyation plays an important role in coordinating the centrosome and cell cycles. Centrosome amplification can occur when the cycles are uncoupled, and this amplification is associated with cancer and with an increase in the levels of chromosomal instability. The aurora kinases A, B, and C are serine/threonine kinases that are active during mitosis. Aurora A is associated with centrosomes, being localized at the centrosome just prior to the onset of mitosis and for the duration of mitosis. Overexpression of aurora A leads to centrosome amplification and cellular transformation. The activity of aurora A is regulated by phosphorlyation and proteasomal degradation.

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“…Breast tumors carrying a BRCA2 mutation showed Aurora-A amplification in 70% of cases as compared with amplification in 22% of sporadic breast tumors [21]. Previously, Aurora-A amplification had been reported in 12% of breast tumors [22].…”

Section: Introductionmentioning

confidence: 97%

Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

Vidarsdóttir¹,

Steingrimsdottir²,

Bödvarsdóttir³

et al. 2010

Invest New Drugs

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Aurora kinases play a vital part in successful mitosis and cell division. Aberrant Aurora-A and -B expression is commonly seen in various types of tumors. Small molecule Aurora inhibitors have already entered clinical trials. Aurora-A amplification has been shown to be associated with breast tumors from BRCA2-mutation carriers and such patients might therefore be candidates for treatment with Aurora kinase inhibitors. There is a need to identify markers that can predict sensitivity to Aurora inhibition. In this study sensitivity to the inhibitor ZM447439 was tested on a panel of 15 non-malignant and malignant epithelial cell lines that differed with respect to BRCA2 and p53 status and related to level of Aurora kinase expression. The IC(50) value for cell survival ranged from 1.9-8.1 μM and was not related to presence or absence of BRCA2 mutation. The levels of Aurora-A and -B expression correlated with each other but sensitivity towards ZM447439 did not correlate with levels of Aurora-A and -B mRNA expression, alone. Cells treated with the Aurora kinase inhibitor completed mitosis but cytokinesis was inhibited resulting in polyploidy and multinucleation. Different levels of polyploidy could not be fully explained by defects in p53. Only cell lines with a combination of high Aurora-A and -B expression, BRCA2 mutation and p53 defects showed more sensitivity towards Aurora inhibition than other cell lines. In conclusion, BRCA2-mutated cells showed variable sensitivity towards Aurora kinase inhibition. The level of sensitivity could not be predicted by Aurora expression levels alone but BRCA2 mutated tumors with high Aurora expression and non-functional p53 are likely candidates for treatment with Aurora inhibitors.

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Aurora-A amplification associated with BRCA2 mutation in breast tumours

Cited by 28 publications

References 35 publications

Aurora-A gene is frequently amplified in basal-like breast cancer

Aurora-A gene is frequently amplified in basal-like breast cancer

Aurora A, centrosome structure, and the centrosome cycle

Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

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