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Updated: Jul 8, 2025
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
Heterogeneity and transcriptional drivers of triple-negative breast cancer
Bojana Jovanović1, Daniel Temko2, Laura E Stevens1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.
Insights
Triple-negative breast cancer (TNBC) is diverse, with limited treatments. This study identifies subtypes and key drivers like PRRX1, offering new research avenues for this aggressive cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents significant heterogeneity, complicating treatment strategies.
- Limited therapeutic options exist for TNBC patients, highlighting the need for deeper biological understanding.
Purpose of the Study:
- To comprehensively characterize TNBC heterogeneity by defining transcriptional, epigenetic, and metabolic subtypes.
- To identify subtype-driving super-enhancers and transcription factors.
- To investigate the role of PRRX1 in driving mesenchymal features in TNBC.
Main Methods:
- Integrated functional and molecular profiling.
- Computational analyses including single-cell RNA sequencing.
- Multiplatform, multiomics analysis of experimental and clinical TNBC samples.
Main Results:
- TNBC subtypes (luminal, basal, mesenchymal) showed relative homogeneity within samples via single-cell RNA sequencing.
- Mesenchymal TNBCs share characteristics with mesenchymal neuroblastoma and rhabdoid tumors.
- The transcription factor PRRX1 was identified as a key driver of mesenchymal TNBC, capable of inducing mesenchymal features in basal cells by reprogramming super-enhancers.
Conclusions:
- PRRX1 is sufficient for inducing mesenchymal features in basal TNBC cells, but not luminal cells.
- PRRX1 is not essential for maintaining the mesenchymal state or cellular viability in TNBC.
- This large-scale multiomics study provides a valuable resource for TNBC research and opens new therapeutic avenues.
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