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

Benjamin A T Rodriguez, Alfred S L Cheng, Pearlly S. Yan, Dustin Potter, Francisco J. Agosto-Perez, Charles L. Shapiro, Hui-ming Huang

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1459-1465
Number of pages7
JournalCarcinogenesis
Volume29
Issue number7
DOIs
StatePublished - 2008
Externally publishedYes

Fingerprint

Epigenetic Repression
Homeobox Genes
Estrogens
Breast Neoplasms
Epigenomics
Neoplasms
Tamoxifen
Estrogen Receptors
Methylation
Disease-Free Survival
Carcinogenesis
Breast
Gene Expression
Recurrence
Cell Line
Genes

ASJC Scopus subject areas

  • Cancer Research

Cite this

Rodriguez, B. A. T., Cheng, A. S. L., Yan, P. S., Potter, D., Agosto-Perez, F. J., Shapiro, C. L., & Huang, H. (2008). Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer. Carcinogenesis, 29(7), 1459-1465. https://doi.org/10.1093/carcin/bgn115

Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer. / Rodriguez, Benjamin A T; Cheng, Alfred S L; Yan, Pearlly S.; Potter, Dustin; Agosto-Perez, Francisco J.; Shapiro, Charles L.; Huang, Hui-ming.

In: Carcinogenesis, Vol. 29, No. 7, 2008, p. 1459-1465.

Research output: Contribution to journalArticle

Rodriguez, BAT, Cheng, ASL, Yan, PS, Potter, D, Agosto-Perez, FJ, Shapiro, CL & Huang, H 2008, 'Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer', Carcinogenesis, vol. 29, no. 7, pp. 1459-1465. https://doi.org/10.1093/carcin/bgn115
Rodriguez BAT, Cheng ASL, Yan PS, Potter D, Agosto-Perez FJ, Shapiro CL et al. Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer. Carcinogenesis. 2008;29(7):1459-1465. https://doi.org/10.1093/carcin/bgn115
Rodriguez, Benjamin A T ; Cheng, Alfred S L ; Yan, Pearlly S. ; Potter, Dustin ; Agosto-Perez, Francisco J. ; Shapiro, Charles L. ; Huang, Hui-ming. / Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer. In: Carcinogenesis. 2008 ; Vol. 29, No. 7. pp. 1459-1465.
@article{17e9bf000fab449db9f68a78a70d09dc,
title = "Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer",
abstract = "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.",
author = "Rodriguez, {Benjamin A T} and Cheng, {Alfred S L} and Yan, {Pearlly S.} and Dustin Potter and Agosto-Perez, {Francisco J.} and Shapiro, {Charles L.} and Hui-ming Huang",
year = "2008",
doi = "10.1093/carcin/bgn115",
language = "English (US)",
volume = "29",
pages = "1459--1465",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer

AU - Rodriguez, Benjamin A T

AU - Cheng, Alfred S L

AU - Yan, Pearlly S.

AU - Potter, Dustin

AU - Agosto-Perez, Francisco J.

AU - Shapiro, Charles L.

AU - Huang, Hui-ming

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=49349088733&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49349088733&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgn115

DO - 10.1093/carcin/bgn115

M3 - Article

C2 - 18499701

AN - SCOPUS:49349088733

VL - 29

SP - 1459

EP - 1465

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 7

ER -