Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.
IF: 17.694
Cited by: 28


It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.


Spatial Transcriptomics

MeSH terms

BRCA1 Protein
Breast Neoplasms
Cell Communication
Cell Differentiation
Cell Transformation, Neoplastic
Mammary Neoplasms, Experimental
Single-Cell Analysis
Stem Cells
Tumor Microenvironment
Tumor Suppressor Protein p53


Bach, Karsten
Pensa, Sara
Zarocsinceva, Marija
Kania, Katarzyna
Stockis, Julie
Pinaud, Silvain
Lazarus, Kyren A
Shehata, Mona
Simões, Bruno M
Greenhalgh, Alice R
Howell, Sacha J
Clarke, Robert B
Caldas, Carlos
Halim, Timotheus Y F
Marioni, John C
Khaled, Walid T

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