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

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.

TGFβ-Mediated induction of SphK1 as a potential determinant in human MDA-MB-231 breast cancer cell bone metastasis

“…To further explore the subtype selectivity, we added a fourth gene set that was recently described as a list of highly correlated up- and down-regulated genes identified from a large meta-analysis of seven independent clinical studies of triple-negative breast cancer (TNBC) (31). This list compiled from the meta-analysis included 20 over-expressed and 20 under-expressed genes in TNBC.…”

Association of Protein Translation and Extracellular Matrix Gene Sets with Breast Cancer Metastasis: Findings Uncovered on Analysis of Multiple Publicly Available Datasets Using Individual Patient Data Approach

“…However, the prognostic importance of many processes may have been missed because: i) the aim of many of the studies was to find a gene signature predictive of outcome, and not the important cellular pathways and processes[15–22], and, ii) other studies only studied a few processes[12,59]; or did not include gene sets from many databases[23]. …”

Genome-Wide Gene Expression Analysis to Identify Epistatic Gene-Pairs Associated with Prognosis of Breast Cancer

“…of Gene-pairs GEO RFS log-rank P There were also seven gene-pairs that were significantly associated with more than one type of survival data (Table 7). By incorporating the differential expression information we derived previously, we may observe that the TNBC patients were noticeably having worse survival outcomes than non-TNBC patients as TNBC is known to be an aggressive breast cancer subtype [43,44]. For example, both GATA3 [45,46] and SERPINA1 were found significantly under-expressed in TNBC cases and the low expressions of both genes were correlated with poor OS and DMFS.…”