Decoding gene regulatory circuitry underlying TNBC chemoresistance reveals biomarkers for therapy response and...

Area of Science:

• Oncology
• Genomics
• Epigenetics

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with poor outcomes due to high metastasis and chemoresistance.
• The underlying mechanisms of chemotherapy resistance in TNBC remain largely unknown.
• Understanding these mechanisms is crucial for developing effective treatment strategies.

Purpose of the Study:

• To identify cell subpopulations and molecular drivers associated with chemoresistance in TNBC.
• To elucidate the epigenetic regulation, specifically H3K27ac modifications, governing chemoresistance gene expression.
• To explore therapeutic targets within transcription factor networks crucial for TNBC survival and chemosensitivity.

Main Methods:

• Analysis of single-cell transcriptome datasets from longitudinal TNBC patient cohorts (chemoresponsive and chemoresistant).
• Genome-wide mapping of H3K27ac to identify super-enhancers and regulatory networks.
• Functional genetic screens to assess the role of identified transcription factors in TNBC cell survival and drug sensitivity.

Main Results:

• Distinct cell subpopulations and their signature genes linked to TNBC chemoresistance were identified.
• Chemoresistance gene expression is regulated by TNBC super-enhancers and associated transcription factor networks.
• A subset of these transcription factors is essential for TNBC cell survival and their inhibition sensitizes cells to chemotherapy.

Conclusions:

• Epigenetic and transcription factor networks play a critical role in TNBC chemoresistance.
• Targeting these networks presents a promising strategy for overcoming treatment resistance.
• This study provides insights for stratifying TNBC patients and developing novel therapeutic approaches.