Abstract P6-05-09: Exosome microRNA contents are altered during breast cancer progression

Abstract

Abstract Background: The progression of breast cancer involves the transformation of normal mammary epithelial cells to ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC). This process is initiated by genetic alterations and characterized by changes to gene expression programs and microenvironmental alterations. However, the specific drivers of DCIS progression to IBC are not well understood nor has an indicator of progression been identified. Exosomes are small secretory vesicles that can contribute to cancer progression by transferring oncogenic factors, such as microRNAs (miRNAs), to surrounding cells in the tumor microenvironment, and enter the circulation to act at distant sites. miRNAs are short noncoding RNAs that regulate the expression of a target messenger RNA (mRNA). Altered regulation by miRNAs is implicated in cancer progression. In this study, we sought to characterize the exosome miRNAs in the MCF10 isogenic model of breast cancer progression in order to identify potential drivers of breast cancer. Methods: Exosomes were isolated from the conditioned media of the MCF10 isogenic cell line model of breast cancer progression representing the following stages: normal, benign proliferative, carcinoma in situ, and invasive carcinoma. RNA was extracted from the exosomes and next generation RNA sequencing was performed. Exosome miRNA expression was validated in breast cancer cell lines and in plasma exosomes collected from a mouse-intraductal transplantation (MIND) model implanted with MCF10DCIS.com (DCIS) cells that can mimic human DCIS progression in vivo. Results: Comparisons were made between differentially expressed miRNAs among each condition (fold change >1.5; Kruskal-Wallis p<0.05,). Twenty-nine miRNAs were differentially expressed among invasive and DCIS exosomes. The expression of 5 oncogenic miRNAs (miR-30c-5p, -210, -182-5p, -200c-3p, and -200b-3p) were consistently increased, while 2 tumor suppressive miRNAs (miR-423-5p and -92b-3p) were consistently decreased with invasive progression. Exosome miRNA expression was confirmed in breast cancer cell lines and mouse plasma exosomes. Conclusion: This work demonstrates that the microRNA contents of exosomes change upon malignant transformation to invasive breast cancer and indicate that certain exosome microRNAs are consistently up- or down-regulated and may contribute to breast cancer progression. Citation Format: Hannafon BN, Gin AL, Behbod F, Ding W-Q. Exosome microRNA contents are altered during breast cancer progression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-05-09.