Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer

• Published in: Science translational medicine Vol. 6; no. 229; p. 229ra41
• Main Authors: Pathiraja, Thushangi N, Nayak, Shweta R, Xi, Yuanxin, Jiang, Shiming, Garee, Jason P, Edwards, Dean P, Lee, Adrian V, Chen, Jian, Shea, Martin J, Santen, Richard J, Gannon, Frank, Kangaspeska, Sara, Jelinek, Jaroslav, Issa, Jean-Pierre J, Richer, Jennifer K, Elias, Anthony, McIlroy, Marie, Young, Leonie S, Davidson, Nancy E, Schiff, Rachel, Li, Wei, Oesterreich, Steffi
• Format: Journal Article
• Language: English
• Published: United States 26.03.2014
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Aromatase Inhibitors - pharmacology; Aromatase Inhibitors - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation - drug effects; Cellular Reprogramming - drug effects; Cellular Reprogramming - genetics; DNA Methylation - drug effects; DNA Methylation - genetics; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; Estrogens - pharmacology; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing - drug effects; Histones - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; MCF-7 Cells; Mice; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Promoter Regions, Genetic; Xenograft Model Antitumor Assays
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.3008326

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.