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

Ryan Lusby, Ziyi Zhang, Arun Mahesh, Vijay K. Tiwari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype characterised by extensive intratumoral heterogeneity, high rates of metastasis and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of chemotherapy resistance in TNBC patients remains poorly understood. Here, leveraging single-cell transcriptome datasets of matched longitudinal TNBC chemoresponsive and chemoresistant patient cohorts, we unravel distinct cell subpopulations intricately associated with chemoresistance and the signature genes defining these populations. Notably, using genome-wide mapping of the H3K27ac mark, we show that the expression of these chemoresistance genes is driven via a set of TNBC super-enhancers and associated transcription factor networks across TNBC subtypes. Furthermore, genetic screens reveal that a subset of these transcription factors is essential for the survival of TNBC cells, and their loss increases sensitivity to chemotherapeutic agents. Overall, our study has revealed epigenetic and transcription factor networks underlying chemoresistance and suggests novel avenues to stratify and improve the treatment of patients with a high risk of developing resistance.

Original languageEnglish
Article number64
Number of pages17
Journalnpj Precision Oncology
Volume8
DOIs
Publication statusPublished - 12 Mar 2024

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