Epigenetic Reprogramming of HOXC10 in Endocrine-Resistant Breast Cancer

Abstract

Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor 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 which 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.

Whole-genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver

“…1A). Our and others' previous studies showed that both c-DMRs and tissue DMRs (t-DMRs) are mostly located at CGI shores rather than at CGIs and that differential DNA methylation at CGI shores strongly correlates with differential gene expression when comparing different tissues as well as normal and tumor tissues (Irizarry et al Hansen et al 2011;Pathiraja et al 2014). Together, those findings suggest that 5hmC could play a particular part in regulating DNA methylation at CGI shores.…”

Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy

“…Enhanced expression of plasticity networks (4,15,16), as well as mediators of EMT (17,18), in the primary tumor has been associated with treatment failure. Information about changes that occur with tumor progression on treatment, however, is not readily available.…”

Role of Epigenetic Modifications in Luminal Breast Cancer

“…For instance, the developmental gene HOXC10 is E-regulated, and hypermethylation of its promoter is associated with resistance to AI therapies [68]. Prevention of AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance [68]. Another example is LSD1, which is highly expressed in ER- breast cancers [47].…”