Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition

Melanie T. Hartsough, Susan E. Clare, Michael Mair, Abdel G. Elkahloun, Dennis Sgroi, C. Kent Osborne, Gary Clark, Patricia S. Steeg

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88 Scopus citations

Abstract

We hypothesize that elevation of Nm23-H1 expression in micrometastatic breast cancer cells may inhibit their metastatic colonization and further invasion, and induce differentiation, thus resulting in a clinical benefit. The current study investigated the possible contribution of DNA methylation to the regulation of Nm23-H1 expression, based on the observation that two CpG islands are present in its promoter. 5-Aza-2′-deoxycytidine (5-Aza-CdR), a DNA methylation inhibitor, increased the Nm23-H1 expression of 5 of 11 human breast carcinoma cell lines in vitro, including 3 of 3 metastatically competent lines. Increased Nm23-H1 expression was accompanied by a reduction in motility in vitro, with minimal effect on proliferation. Both increased Nm23-H1 expression and decreased motility were observed using low (75 nM) concentrations of 5-Aza-CdR. Array analysis of MDA-MB-231 breast carcinoma cells treated with 5-Aza-CdR confirmed the elevation of nm23-H1 mRNA, whereas relatively few other genes exhibited altered expression. Bisulfite sequencing of the two CpG islands in a panel of cell lines and in 20 infiltrating ductal carcinomas revealed that one island (-3090 bp to -3922 bp) exhibited infrequent differential methylation. The data indicate that DNA methylation inhibitors can directly or indirectly cause both elevation of Nm23-H1 expression and decreased function in one aspect of metastasis, motility.

Original languageEnglish (US)
Pages (from-to)2320-2327
Number of pages8
JournalCancer Research
Volume61
Issue number5
StatePublished - Mar 1 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hartsough, M. T., Clare, S. E., Mair, M., Elkahloun, A. G., Sgroi, D., Osborne, C. K., Clark, G., & Steeg, P. S. (2001). Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition. Cancer Research, 61(5), 2320-2327.