APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer

Cell Rep. 2015 Oct 6;13(1):108-121. doi: 10.1016/j.celrep.2015.08.066. Epub 2015 Sep 24.

Abstract

Estrogen receptor α (ERα) is the key transcriptional driver in a large proportion of breast cancers. We report that APOBEC3B (A3B) is required for regulation of gene expression by ER and acts by causing C-to-U deamination at ER binding regions. We show that these C-to-U changes lead to the generation of DNA strand breaks through activation of base excision repair (BER) and to repair by non-homologous end-joining (NHEJ) pathways. We provide evidence that transient cytidine deamination by A3B aids chromatin modification and remodelling at the regulatory regions of ER target genes that promotes their expression. A3B expression is associated with poor patient survival in ER+ breast cancer, reinforcing the physiological significance of A3B for ER action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytidine / metabolism*
  • Cytidine Deaminase / antagonists & inhibitors
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage
  • DNA End-Joining Repair*
  • Deamination
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Minor Histocompatibility Antigens
  • Prognosis
  • Protein Binding
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Survival Analysis
  • Transcription, Genetic
  • Trefoil Factor-1
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Estrogen Receptor alpha
  • Minor Histocompatibility Antigens
  • RNA, Small Interfering
  • TFF1 protein, human
  • Trefoil Factor-1
  • Tumor Suppressor Proteins
  • Cytidine
  • DNA
  • APOBEC3B protein, human
  • Cytidine Deaminase

Associated data

  • GEO/GSE56979
  • GEO/GSE57426