Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer

Thushangi N. Pathiraja, Shweta R. Nayak, Yuanxin Xi, Shiming Jiang, Jason P. Garee, Dean P. Edwards, Adrian V. Lee, Jian Chen, Martin J. Shea, Richard J. Santen, Frank Gannon, Sara Kangaspeska, Jaroslav Jelinek, Jean Pierre J. Issa, Jennifer K. Richer, Anthony Elias, Marie McIlroy, Leonie S. Young, Nancy E. Davidson, Rachel SchiffWei Li, Steffi Oesterreich

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number229ra41
JournalScience translational medicine
Volume6
Issue number229
DOIs
StatePublished - Mar 26 2014

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pathiraja, T. N., Nayak, S. R., Xi, Y., Jiang, S., Garee, J. P., Edwards, D. P., Lee, A. V., Chen, J., Shea, M. J., Santen, R. J., Gannon, F., Kangaspeska, S., Jelinek, J., Issa, J. P. J., Richer, J. K., Elias, A., McIlroy, M., Young, L. S., Davidson, N. E., ... Oesterreich, S. (2014). Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Science translational medicine, 6(229), [229ra41]. https://doi.org/10.1126/scitranslmed.3008326