Limits...
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 PT, Sanus JM, Klein K, Kalimutho M, Shi W, Miranda M, Kutasovic J, Raghavendra A, Madore J, Reid L, Krause L, Chenevix-Trench G, Lakhani SR, Khanna KK - Oncogenesis (2014)

Bottom Line: 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.Particularly, the inhibition of TTK significantly reduced the survival of TNBC cells and synergized with docetaxel in vitro.Prognostication from these metagenes at the mRNA level was limited to ER-positive tumors.

View Article: PubMed Central - PubMed

Affiliation: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Survival of patients stratified by the 8-gene score in the METABRIC data set. The overall survival of patients in the METABRIC data set was analyzed according to the 8-gene score in selected settings in all patients (a) or in ER-positive patients only (b). (a) TP53 mutation was compared in high vs low 8-gene score (split by the median). The expression of the proliferation marker Ki67 was divided by dichotomy across the median, and patients in each of these groups were then stratified according to their 8-gene score (split by quartiles). Disease stages (Stage I—Stage III) were stratified by the median 8-gene score. (b) ER+ Grade 3, ER+ lymph node-negative (LN−) and ER+ LN+ tumors were stratified by the quartiles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4007196&req=5

fig3: Survival of patients stratified by the 8-gene score in the METABRIC data set. The overall survival of patients in the METABRIC data set was analyzed according to the 8-gene score in selected settings in all patients (a) or in ER-positive patients only (b). (a) TP53 mutation was compared in high vs low 8-gene score (split by the median). The expression of the proliferation marker Ki67 was divided by dichotomy across the median, and patients in each of these groups were then stratified according to their 8-gene score (split by quartiles). Disease stages (Stage I—Stage III) were stratified by the median 8-gene score. (b) ER+ Grade 3, ER+ lymph node-negative (LN−) and ER+ LN+ tumors were stratified by the quartiles.

Mentions: Next, we explored the 8-gene score for prognosis in several molecular and histological settings in the METABRIC data set. The survival of patients with tumors with wild-type TP53 was stratified by the 8-gene score (Figure 3a). Patients with mutant TP53, which were mainly of high score, showed worse survival than those with wild-type TP53, suggesting that TP53 mutation is an independent prognostic factor. Patients with tumors with low or high expression of the proliferation marker Ki67 were stratified by the 8-gene score, suggesting that the 8-gene score is independent of proliferation (Figure 3a). We also found that the 8-gene score stratified the survival of patients from all stages of disease (Stage I—Stage III, Figure 3a). We focused on ER+ and found that, as in the case of ER+ Grade 2 tumors (Figure 2c), the 8-gene score stratified the survival of patients with ER+ Grade 3 tumors (Figure 3b). Importantly, the 8-gene score identified ER+LN− and ER+LN+ patients who had poor survival similar to ER−LN− and ER−LN+ patients, respectively (Figure 3b). High 8-gene score identified poor survival of patients with tumors of all PAM50 subtypes, and the prognostication by PAM50 classification was only evident in low 8-gene score tumors (Supplementary Figure 5).


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 PT, Sanus JM, Klein K, Kalimutho M, Shi W, Miranda M, Kutasovic J, Raghavendra A, Madore J, Reid L, Krause L, Chenevix-Trench G, Lakhani SR, Khanna KK - Oncogenesis (2014)

Survival of patients stratified by the 8-gene score in the METABRIC data set. The overall survival of patients in the METABRIC data set was analyzed according to the 8-gene score in selected settings in all patients (a) or in ER-positive patients only (b). (a) TP53 mutation was compared in high vs low 8-gene score (split by the median). The expression of the proliferation marker Ki67 was divided by dichotomy across the median, and patients in each of these groups were then stratified according to their 8-gene score (split by quartiles). Disease stages (Stage I—Stage III) were stratified by the median 8-gene score. (b) ER+ Grade 3, ER+ lymph node-negative (LN−) and ER+ LN+ tumors were stratified by the quartiles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4007196&req=5

fig3: Survival of patients stratified by the 8-gene score in the METABRIC data set. The overall survival of patients in the METABRIC data set was analyzed according to the 8-gene score in selected settings in all patients (a) or in ER-positive patients only (b). (a) TP53 mutation was compared in high vs low 8-gene score (split by the median). The expression of the proliferation marker Ki67 was divided by dichotomy across the median, and patients in each of these groups were then stratified according to their 8-gene score (split by quartiles). Disease stages (Stage I—Stage III) were stratified by the median 8-gene score. (b) ER+ Grade 3, ER+ lymph node-negative (LN−) and ER+ LN+ tumors were stratified by the quartiles.
Mentions: Next, we explored the 8-gene score for prognosis in several molecular and histological settings in the METABRIC data set. The survival of patients with tumors with wild-type TP53 was stratified by the 8-gene score (Figure 3a). Patients with mutant TP53, which were mainly of high score, showed worse survival than those with wild-type TP53, suggesting that TP53 mutation is an independent prognostic factor. Patients with tumors with low or high expression of the proliferation marker Ki67 were stratified by the 8-gene score, suggesting that the 8-gene score is independent of proliferation (Figure 3a). We also found that the 8-gene score stratified the survival of patients from all stages of disease (Stage I—Stage III, Figure 3a). We focused on ER+ and found that, as in the case of ER+ Grade 2 tumors (Figure 2c), the 8-gene score stratified the survival of patients with ER+ Grade 3 tumors (Figure 3b). Importantly, the 8-gene score identified ER+LN− and ER+LN+ patients who had poor survival similar to ER−LN− and ER−LN+ patients, respectively (Figure 3b). High 8-gene score identified poor survival of patients with tumors of all PAM50 subtypes, and the prognostication by PAM50 classification was only evident in low 8-gene score tumors (Supplementary Figure 5).

Bottom Line: 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.Particularly, the inhibition of TTK significantly reduced the survival of TNBC cells and synergized with docetaxel in vitro.Prognostication from these metagenes at the mRNA level was limited to ER-positive tumors.

View Article: PubMed Central - PubMed

Affiliation: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

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.

No MeSH data available.


Related in: MedlinePlus