Abstract B012: Exosome microRNAs are progressively altered and contribute to invasive progression of ductal carcinoma in situ

Abstract

Abstract Ductal carcinoma in situ (DCIS) is a benign breast condition that increases the risk of invasive breast cancer (IBC). Clinically, not all DCIS will progress to IBC and the major drivers of progression are not well understood. The role of small extracellular vesicles, also known as exosomes, is well described in advanced cancers, however, little is known about their role in the invasive progression of in situ breast disease. In this study, we sought to evaluate the role of exosomes and their RNA contents in the progression of DCIS, using the MCF10 isogenic series, in vitro assays and the mouse intraductal model of breast cancer progression. We observed a significant increase of exosome loading of microRNAs (miRNAs) between normal and benign states that increased with each stage. We demonstrate that pro-invasive programs were attenuated when overall exosome and miRNA secretion was inhibited by Rab27A and Dicer knockdown, respectively. Comparisons of exosome miRNA expression changes revealed the greatest differential expression between in situ and invasive cells, with miR-205 being the most significantly different, suggesting a mechanistic role for exosome miRNAs in invasive progression. Modulation of miR-205 levels affected epithelial to mesenchymal transition and the invasive programs in vitro. Progression of DCIS in vivo resulted in increased levels of specific circulating exosome miRNAs, while inhibition of exosome secretion (Rab27A knockdown) attenuated invasive progression and reduced circulating levels of exosome miRNAs. These observations suggest that exosome miRNAs are differentially loaded and expressed, and promote the invasive progression of DCIS and that circulating exosome miRNAs are a potential source of biomarkers of the DCIS to invasive transition. Citation Format: Bethany Hannafon, Samrita Dogra, Sugantha Priya Elayapillai, James Lausen, Matthew Bruns, Fariba Behbod, Amy Gin, Chao Xu, Roy Zhang, Wei-Qun Ding. Exosome microRNAs are progressively altered and contribute to invasive progression of ductal carcinoma in situ [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B012.