Resistance to endocrine therapy poses a serious challenge to the effective treatment of breast cancer. About one-third of all primary breast tumors lack estrogen receptor (ER) expression and are insensitive to endocrine therapy such as antiestrogens or ovarian ablation. This phenotype is associated with the worst prognosis. The mechanisms by which ER gene expression is abrogated are poorly understood. However, several recently reported studies suggest that epigenetic changes via DNA methylation may play a role in silencing expression of the ER gene as well as a variety of other tumor suppressor genes. Furthermore, the enzyme which catalyzes the methylation of CpG dinucleotides, DNA methyltransferase (DNA Mtase) is often overexpressed in cancer cells compared with normal cells, and its expression has been reported to increase with progression in some types of cancer. The studies proposed here address the overall hypothesis that loss of ER expression in some breast cancers is a consequence of loss of ER gene transcription associated with hypermethylation at a CpG island in the 5' regio of the human ER gene. They will further address the premise that increased DNA MTase expression may promote the progression of breast cancer to a hormone-independent phenotype by inhibiting expression of genes, like the ER, which would otherwise suppress that phenotype.
The specific aims i nclude: 1) to establish whether there is a relationship between increased expression of DNA MTase and loss of ER expression in human breast cancer cell lines and tissue specimens; 2) to examine the interaction between DNA methylation and histone acetylation as regulators of ER transcription and expression; and 3) to identify other CpG islands in addition to that of the ER that are consistently hypermethylated in hormone-independent human breast cancer cells since such CpG islands may identify genes that promote a hormone-sensitive phenotype. Taken together these studies should provide new insights into the biology of hormone resistance and possible novel therapeutic targets.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Sathyamoorthy, Neeraja
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Keen, Judith Clancy; Davidson, Nancy E (2003) The biology of breast carcinoma. Cancer 97:825-33
Keen, Judith Clancy; Yan, Lan; Mack, Kelly M et al. (2003) A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2'-deoxycytidine. Breast Cancer Res Treat 81:177-86
Yan, Lan; Nass, Sharyl J; Smith, Dawn et al. (2003) Specific inhibition of DNMT1 by antisense oligonucleotides induces re-expression of estrogen receptor-alpha (ER) in ER-negative human breast cancer cell lines. Cancer Biol Ther 2:552-6
Davidson, Nancy E; Visvanathan, Kala; Emens, Leisha (2003) New findings about endocrine therapy for breast cancer. Breast 12:368-72
Yang, X; Yan, L; Davidson, N E (2001) DNA methylation in breast cancer. Endocr Relat Cancer 8:115-27
Yang, X; Phillips, D L; Ferguson, A T et al. (2001) Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. Cancer Res 61:7025-9
Yan, L; Yang, X; Davidson, N E (2001) Role of DNA methylation and histone acetylation in steroid receptor expression in breast cancer. J Mammary Gland Biol Neoplasia 6:183-92
Yang, X; Ferguson, A T; Nass, S J et al. (2000) Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. Cancer Res 60:6890-4