E2F3 induces DNA damage repair, stem-like properties and therapy resistance in breast cancer

Biochim Biophys Acta Mol Basis Dis. 2023 Dec;1869(8):166816. doi: 10.1016/j.bbadis.2023.166816. Epub 2023 Jul 25.

Abstract

Therapy resistance is a major hurdle to the treatment of human malignant tumors. Both DNA damage repair and stem-like properties contribute to chemoresistance and radioresistance. E2F transcription factor 3 (E2F3) is overexpressed in breast cancer tissues, and promotes proliferation of breast cancer cells. Higher E2F3 level is associated with shorter survival of breast cancer patients. Functional studies further showed that E2F3 promotes S-phage entry, DNA replication, DNA damage repair and stem-like properties. Accordingly, E2F3 knockdown sensitizes breast cancer cells to DNA-damaging agents Adriamycin, Cisplatin, Olaparib and X-ray. Forkhead box M1 (FOXM1) is a downstream molecule of E2F3 signaling, mediating the effects of E2F3 on breast cancer cells. In an m6A methyltransferase METTL14-dependent manner, YTH RNA binding protein F2 (YTHDF2) increase E2F3 mRNA stability and expression, promotes DNA damage repair and induces therapy resistance. These data demonstrate that YTHDF2-E2F3 pathway is a novel target to overcome chemoresistance and radioresistance in breast cancer.

Keywords: Chemoresistance; DNA damage repair; Radioresistance; Stem-like properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • DNA Damage
  • DNA Repair
  • E2F3 Transcription Factor / genetics
  • E2F3 Transcription Factor / metabolism
  • Female
  • Humans
  • Signal Transduction

Substances

  • Cisplatin
  • E2F3 protein, human
  • E2F3 Transcription Factor