Carcinogenesis Advance Access originally published online on May 21, 2008
Carcinogenesis 2008 29(7):1459-1465; doi:10.1093/carcin/bgn115
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Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer
1 Human Cancer Genetics Program
2 Department of Hematology and Oncology, Comprehensive Cancer Center
3 Mathematical Biosciences Institute, The Ohio State University, Columbus, OH 43210, USA
4 Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
* To whom correspondence should be addressed. Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Room 814, Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 8277; Fax: +1 614 292 5995; Email: tim.huang{at}osumc.edu
Several studies have reported that a high expression ratio of HOXB13 to IL17BR predicts tumor recurrence in node-negative, estrogen receptor (ER) 
-positive breast cancer patients treated with tamoxifen. The molecular mechanisms underlying this dysregulation of gene expression remain to be explored. Our epigenetic analysis has found that increased promoter methylation of one of these genes, HOXB13, correlate with the decreased expression of its transcript in breast cancer cell lines (P < 0.005). Transcriptional silencing of this gene can be reversed by a demethylation treatment. HOXB13 is suppressed by the activation of estrogen signaling in ER-positive breast cancer cells. However, treatment with 4-hydroxytamoxifen (4-OHT), an antiestrogen, abrogates the ER-mediated suppression in cancer cells. The notion that this transcriptional induction of HOXB13 occurs in vitro with simultaneous exposure to both estrogen and 4-OHT may provide a biological explanation for its aberrant expression in many node-negative patients undergoing tamoxifen therapy. Interestingly, promoter hypermethylation of HOXB13 is more frequently observed in ER-positive patients with increased lymph node metastasis (P = 0.031) and large tumor sizes (>5 cm) (P = 0.008). In addition, this aberrant epigenetic event is associated with shorter disease-free survival (P = 0.029) in cancer patients. These results suggest that hypermethylation of HOXB13 is a late event of breast tumorigenesis and a poor prognostic indicator of node-positive cancer patients.
Abbreviations: CI, confidence interval; DFS, disease-free survival; E2, 17β-estradiol; ER, estrogen receptor; FBS, fetal bovine serum; HR, hazard ratio; 4-OHT, 4-hydroxytamoxifen; OR, odds ratio; PCR, polymerase chain reaction; PMR, percentage of methylated reference; PR, progesterone receptor; qMSP, quantitative methylation-specific polymerase chain reaction; qRT–PCR, quantitative reverse transcription–polymerase chain reaction
Received March 14, 2008; revised April 29, 2008; accepted May 4, 2008.
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