Seventy percent of breast cancers are classified as estrogen-receptor positive (ER+) and ER is the key proliferative driver in these tumours. Clinically, ER+ patients receive ER-targeted (endocrine) therapies to inhibit ER activity and whilst these agents reduce the risk of recurrence, up to 43% patients develop drug resistance within 15 years. Hence, identification of mechanisms underlying these resistant mechanisms could extend the use of endocrine-therapies. Profound alterations to the genome-wide DNA methylation landscape occur in the early stages of cancer and continue to alter throughout the acquisition of drug resistance. We have previously identified DNA hypermethylation as an important contributor to endocrine-resistance resulting in reduced ER binding and decreased gene expression of key regulators of ER-activity (Stone et al., Nat Comms 2015). Here, we aim to determine whether DNA demethylation agents may be efficacious in reversing endocrine-resistance and restoring sensitivity to endocrine therapy. As a pilot study we have evaluated the efficacy of decitabine, a DNA methyltransferase inhibitor, in combination with endocrine-therapies on the growth of endocrine-resistant patient-derived xenograft (PDX) models (Gar15-13 and HCI-005). Our results demonstrate that decitabine treatment alone reduced the proliferation of these PDX models, with decitabine further augmenting the effect of endocrine-therapies. At end point harvested tumours were assessed for genome-wide methylation alterations using the Illumina MethylationEPIC microarray. We show that decitabine treatment induces DNA demethylation, enriched primarily at promoter and enhancer elements. Furthermore, gene expression profiling indicates an elevation in ER signaling and this increase in ER activity by decitabine may underlie the added efficacy when endocrine-therapy and decitabine are combined. Overall our results provide promise for the potential efficacy of demethylation agents in a preclinical model. Further work is currently being done in different endocrine-resistant patient-derived xenograft models to determine if this may be a suitable therapeutic approach for endocrine resistant ER+ breast cancer.
17 Mar 2019 - 20 Mar 2019