KDM3B-ETF1 fusion gene downregulates LMO2 via the WNT/β-catenin signaling pathway, promoting metastasis of invasive ductal carcinoma

Cancer Gene Ther. 2022 Feb;29(2):215-224. doi: 10.1038/s41417-021-00301-z. Epub 2021 Apr 7.

Abstract

Breast cancer is the most common malignancy for women, with invasive ductal carcinoma being the largest subtype of breast cancers, accounting for 75-80% of cases. However, the underlying mechanism of invasive ductal carcinoma remains unclear. In this study, we investigate the possible effects KDM3B-ETF1 fusion gene has on breast cancer cell metastasis, invasion and its downstream signaling mediators as revealed from RNA sequence data analysis. As predicted, KDM3B-ETF1 expression was increased in breast cancer tissues and cells. Overexpression of KDM3B-ETF1 in cancer cell lines promoted the growth and invasion of breast cancer cells, while KDM3B-ETF1 knockdown showed the opposite effects on malignant cell growth and invasion both in vivo and in vitro as evidenced by cell counting kit-8, Transwell assay and tumor xenograft in nude mice. On the contrary, LIM Domain Only 2 (LMO2) expression was significantly reduced in breast cancer tissues and cells. According to chromatin immunoprecipitation and Western blot analysis, KDM3B-ETF1 targets LMO2 and reduced the expression of LMO2, leading to an increase in WNT/β-catenin signaling pathway and thus promoting invasion. In conclusion, fusion gene KDM3B-ETF1 inhibits LMO2, activates the Wnt/β-catenin signaling pathway that leads to increased breast cancer cell invasion and metastasis, providing a novel insight into developing therapeutic strategies. These results provide novel insights into the molecular mechanism of invasive ductal carcinomas, which may lead to potential therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Carcinoma, Ductal* / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • LIM Domain Proteins
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • LIM Domain Proteins
  • LMO2 protein, human
  • Proto-Oncogene Proteins
  • beta Catenin
  • Jumonji Domain-Containing Histone Demethylases
  • KDM3B protein, human
  • Kdm3b protein, mouse