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Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers.

ABSTRACT: Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs. Methods: Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylation (C/P) genes was used to identify key C/P factors. Results: We established an unconventional APA subtyping system composed of four stable subtypes: 1) luminal androgen receptor (LAR), 2) mesenchymal-like immune-activated (MLIA), 3) basal-like (BL), 4) suppressed (S) subtypes. Patients in the S subtype had the worst disease-free survival comparing to other patients (log-rank p = 0.021). Enriched clinically actionable pathways and putative therapeutic APA events were analyzed among each APA subtype. Furthermore, CPSF1 and PABPN1 were identified as the master C/P factors in regulating APA events and TNBC proliferation. The depletion of CPSF1 or PABPN1 weakened cell proliferation, enhanced apoptosis, resulted in cell cycle redistribution and a reversion of APA events of genes associated with tumorigenesis, proliferation, metastasis and chemosensitivity in breast cancer. Conclusions: Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC.

SUBMITTER: Wang L

PROVIDER: S-EPMC7482814 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers.

Wang Lei L Lang Guan-Tian GT Xue Meng-Zhu MZ Yang Liu L Chen Li L Yao Ling L Li Xiao-Guang XG Wang Peng P Hu Xin X Shao Zhi-Ming ZM

Theranostics 20200821 23

<b>Background:</b> Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs. <b>Methods:</b> Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylatio ...[more]

PMID: 32929364

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Project description:BackgroundAlthough triple-negative breast cancer (TNBC) is associated with an increased risk of recurrence and metastasis, the molecular mechanisms underlying metastasis in TNBC remain unknown. To identify transcriptional changes and genes regulating metastatic progression in TNBC, we compared the transcriptomic profiles of primary and matched metastatic tumors using massively parallel RNA sequencing.MethodsWe performed gene expression profiling using formalin-fixed paraffin-embedded (FFPE) TNBC tissues of patients from two cohorts: the Zurich cohort (n = 31) and the Stavanger cohort (n = 5). Among the 31 patients in the Zurich cohort, 18 had primary TNBC tumors that did not metastasize, and 13 had primary tumors that metastasized (11 paired primary and locoregional recurrences). The Stavanger cohort included five matched primary and metastatic TNBC tumors. Significantly differentially expressed genes (DEGs; absolute fold change ≥2, p < 0.05) were identified and subjected to functional analyses. We investigated if there was any overlap between DEGs from both the cohorts with epithelial-to-mesenchymal-to-amoeboid transition (EMAT) gene signature. xCell was used to estimate relative fractions of 64 immune and stromal cell types in each RNA-seq sample.ResultsIn the Zurich cohort, we identified 1624 DEGs between primary TNBC tumors and matched metastatic lesions. xCell analysis revealed a significantly higher immune scores for metastatic lesions compared to paired primary tumors in the Zurich cohort. We also found significant upregulation of three MammaPrint signature genes (HRASLS, TGFB3 and RASSF7) in primary tumors that metastasized compared to primary tumors that remained metastasis-free. In the Stavanger cohort, we identified 818 DEGs between primary tumors and matched metastatic lesions. No significant differences in xCell immune scores were observed. We found that 21 and 14 DEGs from Zurich and Stavanger cohort, respectively, overlapped with the EMAT gene signature. In both cohorts, genes belonging to the MMP, FGF, and PDGFR families were upregulated in primary tumors compared to matched metastatic lesions.ConclusionsOur results suggest that distinct gene expression patterns exist between primary TNBCs and matched metastatic tumors. Further studies are warranted to explore whether these discrete expression profiles underlie or result from disease status.

Dataset Information

Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers.

Publications

Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers.

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