Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

Biochem Biophys Res Commun. 2013 Aug 9;437(4):557-64. doi: 10.1016/j.bbrc.2013.06.114. Epub 2013 Jul 9.


Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven-nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK-extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway.

Keywords: 5-FU; Breast cancer; Cancer stem cells; ERK1/2; Ell3; Proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Apoptosis
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Fluorouracil / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hyaluronan Receptors / metabolism
  • Isoenzymes / metabolism
  • MAP Kinase Signaling System*
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / cytology
  • RNA, Small Interfering / metabolism
  • Retinal Dehydrogenase / metabolism
  • Transcriptional Elongation Factors / metabolism*


  • ELL3 protein, human
  • Hyaluronan Receptors
  • Isoenzymes
  • RNA, Small Interfering
  • Transcriptional Elongation Factors
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • Fluorouracil