Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer

被引:38
作者
Rodriguez, Benjamin A. T.
Cheng, Alfred S. L. [4 ,5 ]
Yan, Pearlly S.
Potter, Dustin [3 ]
Agosto-Perez, Francisco J.
Shapiro, Charles L. [2 ]
Huang, Tim H. -M. [1 ]
机构
[1] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, Columbus, OH 43210 USA
[2] Ohio State Univ, Ctr Comprehens Canc, Dept Hematol & Oncol, Columbus, OH 43210 USA
[3] Ohio State Univ, Math Biosci Inst, Columbus, OH 43210 USA
[4] Chinese Univ Hong Kong, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China
[5] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China
关键词
D O I
10.1093/carcin/bgn115
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Several studies have reported that a high expression ratio of HOXB13 to IL17BR predicts tumor recurrence in node-negative, estrogen receptor (ER) alpha-positive breast cancer patients treated with tamoxifen. The molecular mechanisms underlying this dys-regulation 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 alpha-positive breast cancer cells. However, treatment with 4-hydroxytamoxifen (4-OHT), an antiestrogen, abrogates the ER alpha-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 alpha-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.
引用
收藏
页码:1459 / 1465
页数:7
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