Resistance to aromatase inhibitors is a major problem in treatment of estrogen receptor (ER)-positive breast cancer. In a study reported in Science Translational Medicine, Pathiraja and colleagues found pervasive DNA hyper- and hypomethylation and enrichment for promoter hypermethylation of developmental genes in two breast cancer cell line models of aromatase inhibitor resistance.
Methylation of the homeobox gene HOXC10 occurred in a CpG island shore overlapping a functional ER binding site, resulting in diminished HOXC10 expression. Blocking of ER signaling resulted in reduced HOXC10 repression in both cell lines and breast tumors, but also induced concurrent recruitment of EZH2 and increases in H3K27me3, promoting a transition to increased DNA methylation and silencing of HOXC10.
Reduction of HOXC10 in vitro and in xenografts resulted in decreased apoptosis and established antiestrogen resistance. Investigation of paired primary and metastatic breast cancer specimens showed that HOXC10 was reduced in tumors that recurred during aromatase inhibitor treatment.
The investigators concluded, “We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas [aromatase inhibitors] induce these genes to cause apoptosis and therapeutic benefit, but long-term [aromatase inhibitor] treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting [aromatase inhibitor]-induced histone and DNA methylation may be beneficial in blocking or delaying [aromatase inhibitor] resistance.” ■
Pathiraja TN, et al: Sci Transl Med 6:229ra41, 2014.