Exploring and Exploiting the Aberrant DNA Methylation Profile of Endocrine-Resistant Breast Cancer

Abstract

we consider how exploring the DNA methylation profile of endocrine-resistant cancer could potentially provide clinically relevant biomarkers to guide new approaches to detection and therapy, as well as advance our understanding of the mechanisms underlying this disease phenotype. It is well established that profound alterations to the genome-wide DNA methylation landscape occur in early stages of cancer initiation, during cancer progression and also throughout the acquisition of drug resistance [6,7]. These alterations are characterized by global DNA hypomethylation, which promotes genome instability and oncogene activation, and local DNA hypermethylation, typically at CpG island promoters of tumor suppressor genes, which is associated with gene silencing. The detection of aberrant DNA methylation has emerged as the most promising and best developed class of epigenetic biomarkers for cancer detection [8]. Differentially methylated regions (DMRs) of DNA have been successfully characterized as biomarkers for early detection of disease, tumor classification and response to treatment in numerous cancer subtypes (as reviewed in [8,9]). The major advantage of DNA methylation biomarkers is that DNA is inherently stable and can be obtained from numerous sources including tissue, plasma, saliva and urine [9,10]. In patients with metastatic breast cancer, genomic DNA fragments, most likely derived from necrotic or apoptotic cancer cells that carry cancer-specific epigenetic alterations, can be detected and isolated from serum. The concentration of cellfree circulating DNA in plasma from healthy individuals ranges from 10–20 ng/ml, which can increase up to 1000 ng/ml in patients with metastatic disease [11]. Using cell-free circulating DNA, multiple regions of cancer-specific hypermethylated DNA can be readily amplified using The steroid hormone estrogen is critical for the development and maintenance of the female reproductive system and also has a fundamental role in breast cancer pathogenesis. In 70% of all breast cancer cases, activation of the estrogen receptor (ER) drives cancer cell proliferation and subsequent tumor development [1,2]. ER-positive breast cancer subtypes (luminal A and luminal B) are associated with better overall survival compared with ER-negative subtypes (basal, HER2 and claudin), which is in part due to the widespread use of adjuvant endocrine therapy [3]. Endocrine therapies that serve to inhibit ER signaling, such as the selective ER modulator tamoxifen, have been used effectively for almost 40 years and have been proven to reduce the risk of disease recurrence [2,4]. Nevertheless, 28% of luminal A and 43% of luminal B breast cancer patients will exhibit intrinsic or acquired drug resistance and develop distant metastases up to 15 years after initial diagnosis [4]. Metastases most commonly form in the bone, brain, lungs or liver, ruling out surgical intervention for most patients. Current second-line therapeutic strategies remain limited and responses are often short-lived. As such, the median duration of survival from time of relapse is 2.2 and 1.6 years for luminal A and luminal B breast cancer patients, respectively [5]. Endocrine-resistant disease makes up almost a quarter of all breast cancer cases and represents one of the most significant obstacles in breast cancer treatment. Therefore, there is an obvious and urgent need to improve both the way ER-positive breast cancer patients are stratified as responders to endocrine therapy and how endocrine-resistant disease is managed therapeutically. Ideally, this could be achieved with robust biomarkers predictive of treatment response that, in the case of metastatic disease, could be profiled using noninvasive assays of the blood in the absence of a tumor biopsy. Here,