BRCA1/FANCD2/BRG1-Driven DNA Repair Stabilizes the Differentiation State of Human Mammary Epithelial Cells

Mol Cell. 2016 Jul 21;63(2):277-292. doi: 10.1016/j.molcel.2016.05.038. Epub 2016 Jun 30.

Abstract

An abnormal differentiation state is common in BRCA1-deficient mammary epithelial cells, but the underlying mechanism is unclear. Here, we report a convergence between DNA repair and normal, cultured human mammary epithelial (HME) cell differentiation. Surprisingly, depleting BRCA1 or FANCD2 (Fanconi anemia [FA] proteins) or BRG1, a mSWI/SNF subunit, caused HME cells to undergo spontaneous epithelial-to-mesenchymal transition (EMT) and aberrant differentiation. This also occurred when wild-type HMEs were exposed to chemicals that generate DNA interstrand crosslinks (repaired by FA proteins), but not in response to double-strand breaks. Suppressed expression of ΔNP63 also occurred in each of these settings, an effect that links DNA damage to the aberrant differentiation outcome. Taken together with somatic breast cancer genome data, these results point to a breakdown in a BRCA/FA-mSWI/SNF-ΔNP63-mediated DNA repair and differentiation maintenance process in mammary epithelial cells that may contribute to sporadic breast cancer development.

Keywords: BRCA1; BRG1; EMT; FANCD2; breast cancer; cisplatin; crosslink repair.

Publication types

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

MeSH terms

  • Acetaldehyde / pharmacology
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control*
  • Cell Differentiation*
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cisplatin / pharmacology
  • DNA Damage*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Repair*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism*
  • Female
  • Formaldehyde / pharmacology
  • Humans
  • Mammary Glands, Human / drug effects
  • Mammary Glands, Human / metabolism*
  • Mammary Glands, Human / pathology
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phenotype
  • RNA Interference
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Nuclear Proteins
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Formaldehyde
  • SMARCA4 protein, human
  • DNA Helicases
  • Acetaldehyde
  • Cisplatin