Alternative Promoters Drive Transcriptomic Reprogramming and Prognostic Stratification in TNBC

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Triple-Negative Breast Cancer (TNBC) is aggressive and heterogeneous, with gene expression poorly understood at the pre-transcriptional level.
• Short-read RNA sequencing has limitations in resolving transcript diversity, hindering the study of alternative promoter usage.
• Alternative promoter usage is a critical regulatory mechanism in cancer, yet remains underexplored in TNBC.

Purpose of the Study:

• To investigate promoter-level quantification for inferring active promoter usage in TNBC.
• To identify TNBC-specific and subtype-enriched Active Alternative Promoters (AAPs).
• To explore the prognostic value of alternative promoter activity in TNBC patient outcomes.

Main Methods:

• Utilized RNA-sequencing data from 360 TNBC tumors and 88 normal tissues for promoter-level quantification.
• Integrated data with H3K4me3 and H3K27ac ChIP-seq to analyze epigenetic modifications.
• Developed a prognostic model incorporating promoter activities and clinical variables.

Main Results:

• Identified TNBC-specific AAPs and a key promoter switch in the HDAC9 gene, epigenetically regulated.
• Discovered subtype-specific alternative promoter activities (e.g., SEC31A, AKAP9) not evident at the gene expression level.
• Alternative promoters of HUWE1 and FTX independently predicted relapse-free survival (RFS) in TNBC.

Conclusions:

• Promoter switching in genes like HDAC9 is a tumor-specific regulatory mechanism in TNBC.
• Alternative promoter analysis provides insights into TNBC heterogeneity and regulation.
• Promoter activity represents a promising biomarker for improving TNBC risk stratification and predicting patient prognosis.