Journal Article

Epigenetic repression of the estrogen-regulated <i>Homeobox B13</i> gene in breast cancer

Benjamin A.T. Rodriguez, Alfred S.L. Cheng, Pearlly S. Yan, Dustin Potter, Francisco J. Agosto-Perez, Charles L. Shapiro and Tim H.-M. Huang

in Carcinogenesis

Volume 29, issue 7, pages 1459-1465
Published in print July 2008 | ISSN: 0143-3334
Published online May 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn115
Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer

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Several studies have reported that a high expression ratio of HOXB13 to IL17BR predicts tumor recurrence in node-negative, estrogen receptor (ER) α-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 ERα-positive breast cancer cells. However, treatment with 4-hydroxytamoxifen (4-OHT), an antiestrogen, abrogates the ERα-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 ERα-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.

Journal Article.  4644 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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