Aromatase inhibitors (AI) are use in the treatment of estrogen receptor (ER) positive breast cancer, but tumors often develop resistance to these. In the latest edition of Science Translational Medicine Thushangi Pathiraja and colleagues identified ways in which cancer cells develop this resistance by ’epigenic reprogramming’ – using the mechanisms for ‘switching off ‘ genes seen in normal cells as they differentiate and take on specialist functions. The NIH-funded study found methylation of DNA (in a ‘CpG shore’ which overlapped with a ER binding site) resulting in reduced expression of the HOXC10 gene in breast cancer cell lines. Even when ER signaling was blocked in cell lines and tumors this only resulted in short-term HOXC10 expression and the cells went on to increas DNA methylation and silencing of HOXC10.
The study linked reduced HOXC10 with decreased apoptosis and caused antiestrogen resistance. An analysis of paired primary and metastatic breast cancer specimens showed HOXC10 was reduced in tumors that recurred during AI treatment.
Drawing on this study and previous work the authors propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival. AI treatments induce these genes to cause short-term apoptosis and clinical benefit, but long-term AI treatment results in permanent repression of these genes via methylation resulting in resistance. Therefore the authors propose future investigation of therapies aimed at inhibiting AI-induced histone and DNA methylation in order to block or slow down AI resistance.
Pathiraja TN, Nayak SR, Xi Y, et al. Epigenetic Reprogramming of HOXC10 in Endocrine-Resistant Breast Cancer Sci. Transl. Med. 6, 229ra41 (2014).
HOXC10 in CancerGenetics Web