Expression of DNA methyl-transferase (DMT) and the cell cycle in human breast cancer cells

Sharyl J. Nass, Anne T. Ferguson, Dorraya El-Ashry, William G. Nelson, Nancy E. Davidson

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Estrogen receptor (ER)-negative breast cancer cells display extensive methylation of the ER gene CpG island and elevated DNA methyltransferase (DMT) expression compared to ER-positive cells. The present study demonstrates that DMT protein levels tightly correlate with S phase fraction in ER-positive cells, whereas ER-negative cells express DMT throughout the cell cycle. In addition, levels of p21(CIP1), which disrupts DMT binding to PCNA, are inversely correlated with DMT levels. Therefore increased DMT expression in ER-negative cells is not simply due to elevated S-phase fraction, but rather to more complex changes that allow cells to escape normal cell cycle-dependent controls on DMT expression. Because ER-negative breast tumors often have activated growth factor pathways, the impact of these pathways on DMT expression was examined in ER-positive cells. Stable transfection with fibroblast growth factors (FGFs) 1 and 4 led to increased DMT expression that could not be accounted for by a shift in S phase fraction. Elevated DMT protein expression in FGF-transfectants was accompanied by a significant decrease in p21, again suggesting a reciprocal relationship between these two proteins. However, acquisition of an estrogen-independent phenotype, even in conjunction with elevated DMT levels, was not sufficient to promote ER gene silencing via methylation. These results indicate that multiple steps are required for de novo methylation of the ER CpG island.

Original languageEnglish
Pages (from-to)7453-7461
Number of pages9
JournalOncogene
Volume18
Issue number52
StatePublished - Dec 9 1999
Externally publishedYes

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Keywords

  • Breast cancer
  • DNA methylation
  • Estrogen receptor
  • p21
  • S phase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Nass, S. J., Ferguson, A. T., El-Ashry, D., Nelson, W. G., & Davidson, N. E. (1999). Expression of DNA methyl-transferase (DMT) and the cell cycle in human breast cancer cells. Oncogene, 18(52), 7453-7461.