Some of our brightest epigenetics researchers from the Garvan Institute in Sydney have identified new mechanisms by which oestrogen receptor positive breast cancers become resistant to hormone therapy. See their publication this month in Nature Communications.
While hormone therapy, such as tamoxifen, has been widely used for decades and has significantly improved survival for patients with oestrogen receptor (ER or ESR1) positive disease, approximately one-third of patients acquire drug resistance and develop disease recurrence within 15 years.
The mechanisms that lead to resistance remain elusive, and so Dr Andrew Stone, Dr Elena Zotenko, Professor Susan Clark and colleagues collaborated with researchers at Cardiff University in Wales, who had developed three cell lines that were each resistant to a different endocrine therapy. They undertook a genome-wide DNA methylation study to see if common epigenetic resistance mechanisms emerged.
Strikingly, they found significant hypermethylation in regulatory regions or enhancer regions of the resistant genome, where the oestrogen receptor binds to DNA and controls oestrogen regulated genes. Methylation can silence gene expression, so methylation of enhancer regions could potentially impact the entire oestrogen-regulated expression network, thereby suppressing oestrogen signalling. Using data from The Cancer Genome Atlas (TCGA), which catalogues methylation profiling and RNA sequencing information on thousands of clinical samples, including breast cancers, they confirmed that hypermethylation of oestrogen receptor responsive enhancers correlated with downregulation of corresponding gene expression.
They extended their study to clinical samples, examining specific enhancer regions in breast cancers from patients who had received tamoxifen for five years; they compared methylation profiles between primary tumours of patients who had and hadn’t relapsed and also compared the recurrent tumours with the primary tumours. The enhancer regions were markedly unmethylated in patients who did not go on to relapse; slightly methylated in patients who did go on to relapse; and heavily methylated in those patients after relapse.
These novel findings were published this month in Nature Communications and have potential implications for the clinical management of resistant disease: enhancer methylation profiling may help predict which patients are likely to recur, and further exploration of this resistance mechanism may aid in identifying novel therapeutic targets or developing alternative therapeutic strategies (such as demethylating agents) for endocrine resistant disease.