Single-Cell Transcriptomic Profiling of Tamoxifen Resistance in Breast Cancer Identifies PTAFR and Dysregulated Transcriptional Programs

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Synopsis of the BIS91DC01404 Minor Project

Om Prakash · Accepted Answer

Endocrine resistance remains a major barrier to successful treatment of estrogen-receptor–positive (ER⁺) breast cancer. Although bulk transcriptomic studies have identified several resistance-associated pathways, the cellular heterogeneity and regulatory programs that drive tamoxifen escape remain incompletely understood. Here, we performed an independent single-cell RNA sequencing (scRNA-seq) reanalysis of the GSE195610 isogenic breast cancer model to delineate transcriptional states underlying the acquisition of tamoxifen resistance. After rigorous quality control and integration of 8,908 high-quality cells, we identified 13 transcriptionally distinct subpopulations spanning sensitive, intermediate, and resistant conditions.

Differential expression and transcription factor (TF) activity inference uncovered a resistance-associated signature enriched for inflammatory signaling, cytoskeletal remodeling, and widespread transcriptional activation. Notably, we identified a PTAFR-high subpopulation uniquely enriched in resistant cells, accompanied by elevated expression of EHF, EPB41L2, DUSP6, TUBA4A, and CITED1. Although PTAFR was expressed in a minority of resistant cells, its extremely high fold-change and spatial localization suggest it marks a specialized, transcriptionally distinct cell subset rather than serving as a universal resistance driver. Pathway enrichment highlighted strong activation of RNA polymerase II–dependent transcription, RNA metabolism, and stress-response programs, indicating pervasive transcriptional rewiring during resistance acquisition.

Together, this analysis provides a high-resolution map of cellular heterogeneity in tamoxifen resistance, identifies PTAFR-high subpopulations as candidates for targeted investigation, and highlights transcriptional deregulation as a central feature of endocrine escape. These findings refine our understanding of resistance biology and provide a framework for future mechanistic and functional validation studies.

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Single-Cell Transcriptomic Profiling of Tamoxifen Resistance in Breast Cancer Identifies PTAFR and Dysregulated Transcriptional Programs

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