Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer

Cell. 2019 Jun 27;178(1):135-151.e19. doi: 10.1016/j.cell.2019.06.002.


Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

Keywords: BRCA1; CtIP; EMT; HES1; ICL repair; NUMB; breast cancer; cell fate; cisplatin; mouse model; single-cell analysis; transdifferentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Breast Neoplasms / chemically induced
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Differentiation / genetics
  • Cell Transdifferentiation / genetics*
  • Cell Transformation, Neoplastic
  • DNA Damage / genetics*
  • DNA Repair / genetics*
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Mammary Glands, Animal / pathology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Transcription Factor HES-1 / metabolism
  • Transfection


  • BRCA1 Protein
  • BRCA1 protein, human
  • Brca1 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Numb protein, human
  • Transcription Factor HES-1
  • HES1 protein, human