Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors

Nat Commun. 2021 Mar 9;12(1):1502. doi: 10.1038/s41467-021-21783-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Communication / physiology
  • Cell Differentiation / physiology
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Female
  • Humans
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mutation
  • Phenobarbital / metabolism*
  • Single-Cell Analysis / methods*
  • Stem Cells / pathology*
  • Stem Cells / physiology
  • Tumor Microenvironment / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Brca1 protein, mouse
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Phenobarbital