TY - JOUR
T1 - Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer
AU - Pathiraja, Thushangi N.
AU - Nayak, Shweta R.
AU - Xi, Yuanxin
AU - Jiang, Shiming
AU - Garee, Jason P.
AU - Edwards, Dean P.
AU - Lee, Adrian V.
AU - Chen, Jian
AU - Shea, Martin J.
AU - Santen, Richard J.
AU - Gannon, Frank
AU - Kangaspeska, Sara
AU - Jelinek, Jaroslav
AU - Issa, Jean Pierre J.
AU - Richer, Jennifer K.
AU - Elias, Anthony
AU - McIlroy, Marie
AU - Young, Leonie S.
AU - Davidson, Nancy E.
AU - Schiff, Rachel
AU - Li, Wei
AU - Oesterreich, Steffi
PY - 2014/3/26
Y1 - 2014/3/26
N2 - Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.
AB - Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.
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U2 - 10.1126/scitranslmed.3008326
DO - 10.1126/scitranslmed.3008326
M3 - Article
C2 - 24670685
AN - SCOPUS:84899096068
SN - 1946-6234
VL - 6
JO - Science translational medicine
JF - Science translational medicine
IS - 229
M1 - 229ra41
ER -