Meta-analysis of the global gene expression profile of triple-negative breast cancer identifies genes for the prognostication and treatment of aggressive breast cancer

Al-Ejeh, F., Simpson, P. T., Saunus, J. M., Klein, K., Kalimutho, M., Shi, W., Miranda, M., Kutasovic, J., Raghavendra, A., Madore, J., Reid, L., Krause, L., Chenevix-Trench, G., Lakhani, S. R. and Khanna, K. K. (2014) Meta-analysis of the global gene expression profile of triple-negative breast cancer identifies genes for the prognostication and treatment of aggressive breast cancer. Oncogenesis, 3 e100-e100. doi:10.1038/oncsis.2014.14


Author Al-Ejeh, F.
Simpson, P. T.
Saunus, J. M.
Klein, K.
Kalimutho, M.
Shi, W.
Miranda, M.
Kutasovic, J.
Raghavendra, A.
Madore, J.
Reid, L.
Krause, L.
Chenevix-Trench, G.
Lakhani, S. R.
Khanna, K. K.
Title Meta-analysis of the global gene expression profile of triple-negative breast cancer identifies genes for the prognostication and treatment of aggressive breast cancer
Journal name Oncogenesis   Check publisher's open access policy
ISSN 2157-9024
Publication date 2014-04-21
Sub-type Article (original research)
DOI 10.1038/oncsis.2014.14
Open Access Status DOI
Volume 3
Start page e100
End page e100
Total pages 12
Place of publication New York, NY United States
Publisher Nature Publishing Group
Collection year 2015
Language eng
Formatted abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking expression of estrogen and progesterone receptors (ER/PR) and HER2, thus limiting therapy options. We hypothesized that meta-analysis of TNBC gene expression profiles would illuminate mechanisms underlying the aggressive nature of this disease and identify therapeutic targets. Meta-analysis in the Oncomine database identified 206 genes that were recurrently deregulated in TNBC compared with non-TNBC and in tumors that metastasized or led to death within 5 years. This ‘aggressiveness gene list’ was enriched for two core functions/metagenes: chromosomal instability (CIN) and ER signaling metagenes. We calculated an ‘aggressiveness score’ as the ratio of the CIN metagene to the ER metagene, which identified aggressive tumors in breast cancer data sets regardless of subtype or other clinico-pathological indicators. A score calculated from six genes from the CIN metagene and two genes from the ER metagene recapitulated the aggressiveness score. By multivariate survival analysis, we show that our aggressiveness scores (from 206 genes or the 8 representative genes) outperformed several published prognostic signatures. Small interfering RNA screen revealed that the CIN metagene holds therapeutic targets against TNBC. Particularly, the inhibition of TTK significantly reduced the survival of TNBC cells and synergized with docetaxel in vitro. Importantly, mitosis-independent expression of TTK protein was associated with aggressive subgroups, poor survival and further stratified outcome within grade 3, lymph node-positive, HER2-positive and TNBC patients. In conclusion, we identified the core components of CIN and ER metagenes that identify aggressive breast tumors and have therapeutic potential in TNBC and aggressive breast tumors. Prognostication from these metagenes at the mRNA level was limited to ER-positive tumors. However, we provide evidence that mitosis-independent expression of TTK protein was prognostic in TNBC and other aggressive breast cancer subgroups, suggesting that protection of CIN/aneuploidy drives aggressiveness and treatment resistance.
Keyword Triple negative breast cancer
Aggressive breast cancer
Therapeutic targets
Kinetochore attachment
Chromosome Segregation
Chromosomal instability
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
School of Medicine Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 12 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 21 times in Scopus Article | Citations
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Created: Mon, 17 Aug 2015, 18:43:19 EST by Dr Jodi Saunus on behalf of UQ Centre for Clinical Research