Epigenetic silencing of maspin gene expression in human breast cancers

Frederick E. Domann, Judd C. Rice, Mary J C Hendrix, Bernard W Futscher

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Maspin is a tumor suppressor whose expression is lost in many advanced breast cancers. Maspin has been shown to inhibit cell motility, invasion and metastasis; however, its precise role in normal mammary epithelium remains to be elucidated. Although expression of maspin mRNA is low or absent in most human breast cancer cells, the maspin gene is rarely re-arranged or deleted. We hypothesized that aberrant cytosine methylation and chromatin condensation of the maspin promoter participates in the silencing of maspin expression during neoplastic progression. To test this hypothesis, we compared cultured normal human mammary epithelial cells (HMECs) to 9 cultured human breast cancer cell lines. HMECs expressed maspin mRNA and displayed a completely non-methylated maspin gene promoter with an open chromatin structure. In contrast, 7 of 9 breast cancer cell lines had no detectable maspin expression and 6 of these 7 maspin-negative breast cancer cell lines also displayed an aberrant pattern of cytosine methylation of the maspin promoter. Interestingly, the maspin promoter was completely methylated in maspin-negative normal peripheral blood lymphocytes. This indicates that the maspin promoter is not a functional CpG island and that cytosine methylation of this region may contribute to normal tissue- restricted gene expression. Chromatin accessibility studies with MCF-7 cells, which lack maspin expression and have a methylated maspin promoter, showed a closed chromatin structure compared with HMECs. Moreover, maspin gene expression could be re-activated in MCF-7 cells by treatment with 5- aza-2'-deoxycytidine, a DNA demethylating agent. Thus, aberrant cytosine methylation and heterochromatinization of the maspin promoter may silence maspin gene expression, thereby contributing to the progression of human mammary cancer. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)805-810
Number of pages6
JournalInternational Journal of Cancer
Volume85
Issue number6
DOIs
StatePublished - 2000

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Epigenomics
Breast Neoplasms
Gene Expression
Cytosine
Methylation
Chromatin
Breast
SERPIN-B5
Epithelial Cells
decitabine
MCF-7 Cells
Cell Line
Messenger RNA
CpG Islands

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Epigenetic silencing of maspin gene expression in human breast cancers. / Domann, Frederick E.; Rice, Judd C.; Hendrix, Mary J C; Futscher, Bernard W.

In: International Journal of Cancer, Vol. 85, No. 6, 2000, p. 805-810.

Research output: Contribution to journalArticle

Domann, Frederick E. ; Rice, Judd C. ; Hendrix, Mary J C ; Futscher, Bernard W. / Epigenetic silencing of maspin gene expression in human breast cancers. In: International Journal of Cancer. 2000 ; Vol. 85, No. 6. pp. 805-810.
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