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.
Highlights
Estrogen and progesterone receptors (ER and PR) and HER2 are standard biomarkers used in clinical practice to aid the histopathological classification of breast cancer and management decisions
triple-negative breast cancer (TNBC) are more sensitive to chemotherapy than hormone receptor-positive tumors, because they are generally more proliferative, and pathological complete responses after chemotherapy are more likely in TNBC than in non-TNBC.[1,2]
We found that TTK inhibitor (TTKi) synergized with docetaxel at very low doses in the treatment of TNBC cell lines that overexpress TTK in comparison with cell lines that do not (Figure 7b), and that this combination induced apoptotic cell death (Figure 7c)
Summary
Estrogen and progesterone receptors (ER and PR) and HER2 are standard biomarkers used in clinical practice to aid the histopathological classification of breast cancer and management decisions. Hormone receptor- and HER2-positive tumors benefit from tamoxifen and anti-HER2 therapies, respectively. There are currently no targeted drug therapies for management of triple-negative breast cancer (TNBC), which lacks the expression of hormone receptors and HER2. TNBCs are more sensitive to chemotherapy than hormone receptor-positive tumors, because they are generally more proliferative, and pathological complete responses after chemotherapy are more likely in TNBC than in non-TNBC.[1,2] Paradoxically, TNBC is associated with poorer survival than non-TNBC, owing to more frequent relapse in TNBC patients with residual disease.[1,2] Only
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