Deciphering the gene regulatory circuitry governing chemoresistance in Triple-Negative Breast Cancer

ABSTRACT Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, due in part to 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, using single-cell transcriptome datasets of matched longitudinal TNBC chemoresponsive and chemoresistant patient cohorts, we discover cell subpopulations associated with chemoresistance and the signature genes defining these populations. Notably, we show that the expression of these chemoresistance genes is driven via a set of TNBC super-enhancers and 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 transcriptional regulatory networks underlying chemoresistance and suggests novel avenues to stratify and improve the treatment of patients with a high risk of developing resistance.