Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer unresponsive to traditional receptor-targeted treatments, leading to a disproportionate number of deaths. Invasive breast cancer is believed to evolve from non-invasive ductal carcinoma in situ (DCIS). Detection of triple-negative DCIS (TN-DCIS) is challenging, therefore strategies to study molecular events governing progression of pre-invasive TN-DCIS to invasive TNBC are needed. Here, we study a canine TN-DCIS progression and investigate the DNA methylation landscape of normal breast tissue, atypical ductal hyperplasia (ADH), DCIS and invasive breast cancer. We report hypo- and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration. DNA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage. Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DCIS. Changes in DNA methylation during TN-DCIS progression in this canine model correspond with gene expression patterns in human breast tissues. This study provides evidence for utilizing methylation status of gene candidates to define late-stage (DCIS and invasive), invasive stage only or DCIS stage only of TN-DCIS progression.
Highlights
Triple-negative breast cancer (TNBC) is a subtype of breast cancer unresponsive to traditional receptortargeted treatments, leading to a disproportionate number of deaths
Known as www.nature.com/scientificreports invasive ductal carcinoma (IDC), is a tumor that started in the milk duct and has invaded tissues of the surrounding breast and potentially other distant sites[37] (Fig. 1A)
Epigenetic alterations, changes in DNA methylation that occur throughout these stages, could distinguish stages and be potentially used to predict progression from atypical ductal hyperplasia (ADH) to ductal carcinoma in situ (DCIS) and subsequently to IDC
Summary
Triple-negative breast cancer (TNBC) is a subtype of breast cancer unresponsive to traditional receptortargeted treatments, leading to a disproportionate number of deaths. It has been suggested that TN-DCIS-derived tumors proliferate twice as fast as luminal A and three times faster than HER2-positive tumors, increasing its metastatic potential to other tissues[11] These unique molecular events have hindered early detection of TNBC and have limited the prospect of preventing this lethal cancer. Dogs and humans share many of the same breast cancer risk factors including aging, progesterone exposure, obesity in early life, poor diet, and mutations in BRCA genes[12,16,17]. They undergo similar treatments against breast cancer. Given the many shared features of canine and human breast cancer and the high homology between the canine and human genome, studying companion dogs offers an outstanding opportunity to examine TNBC biology
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