Transcriptome Analysis of Triple-Negative Breast Cancer Reveals an Integrated mRNA-lncRNA Signature with Predictive and Prognostic Value

Abstract

While recognized as a generally aggressive disease, triplenegative breast cancer (TNBC) is highly diverse in different patients with variable outcomes. In this prospective observational study, we aimed to develop an RNA signature of TNBC patients to improve risk stratification and optimize the choice of adjuvant therapy. Transcriptome microarrays for 33 paired TNBC and adjacent normal breast tissue revealed tumor-specific mRNAs and long noncoding RNAs (lncRNA) that were associated with recurrence-free survival. Using the Cox regression model, we developed an integrated mRNA-lncRNA signature based on the mRNA species for FCGR1A, RSAD2, CHRDL1, and the lncRNA species for HIF1A-AS2 and AK124454. The prognostic and predictive accuracy of this signature was evaluated in a training set of 137 TNBC patients and then validated in a second independent set of 138 TNBC patients. In addition, we enrolled 82 TNBC patients who underwent taxane-based neoadjuvant chemotherapy (NCT) to further verify the predictive value of the signature. In both the training and validation sets, the integrated signature had better prognostic value than clinicopathologic parameters. We also confirmed the interaction between the administration of taxane-based NCT and different risk groups. In the NCT cohort, patients in the lowrisk group were more likely to achieve pathologic complete remission after taxane-based NCT (P ¼ 0.014). Functionally, we showed that HIF1A-AS2 and AK124454 promoted cell proliferation and invasion in TNBC cells and contributed there to paclitaxel resistance. Overall, our results established an integrated mRNA-lncRNA signature as a reliable tool to predict tumor recurrence and the benefit of taxane chemotherapy in TNBC, warranting further investigation in larger populations to help frame individualized treatments for TNBC patients.

Upregulation of LINC00319 indicates a poor prognosis and promotes cell proliferation and invasion in cutaneous squamous cell carcinoma

“…[10][11][12] Previous studies have showed that LINC00319 is involved in the occurrence and development of lung cancer. [10][11][12] Previous studies have showed that LINC00319 is involved in the occurrence and development of lung cancer.…”

Long non-coding RNAs in anti-cancer drug resistance

“…Triple-negative breast cancer account for one fifth of all breast cancers. Jiang et al reported lncRNA HIF1A-AS2 and AK124454 contributed to paclitaxel resistance in triple-negative breast cancer through transcriptome analysis [66]. …”

Insights from Global Analyses of Long Noncoding RNAs in Breast Cancer

“…However, this signature was limited by the number of probes covering lncRNA loci (195 lncRNAs were differentially expressed between normal and tumor) on the Affymetrix Human Transcriptome Array 2.0 implying that this signature can be improved if developed with RNAseq data. Functionally, they confirmed that the two lncRNAs in the signature—HIF1A-AS2 and AK124454—promote proliferation, invasion, and paclitaxel resistance [89]. …”

“…Jiang et al performed a prospective observational study that demonstrated an integrated mRNA-lncRNA signature had better prognostic value to predict recurrence-free survival and pathologic complete remission after taxane-based neoadjuvant chemotherapy than clinicopathologic parameters in a cohort of 275 TNBC patients [89]. However, this signature was limited by the number of probes covering lncRNA loci (195 lncRNAs were differentially expressed between normal and tumor) on the Affymetrix Human Transcriptome Array 2.0 implying that this signature can be improved if developed with RNAseq data.…”