Abstract
Abstract Bone is the most common site for breast cancer (BC) metastasis and relapse. Bone metastasis (BM) causes considerable complications due to osteoclast-mediated bone resorption. Current treatment for osteolysis in BM is limited due to their side effects and inability to extend the patients’ survival. Thus, there is an urgent need for developing early predictive markers and alternative therapies for BC-BM. Recently, circulating miRNAs have been found to harbor great potential for diagnostic and prognostic purposes. Due to the low stability of cell-free RNA in serum, these circulating miRNAs exist mostly in a form of membrane-wrapped extracellular vesicles (EVs) and they play important roles in cancer progression. In this study, we aim to identify EVs derived-miRNA from serum of BC patients as biomarkers for diagnosis and prognosis of BC-BM. To find the circulating miRNAs that are associated with BC-BM, we applied a four-layer screening system combining bioinformatic analyses and experimental verification. Firstly, 85 BC associated circulating miRNAs were identified to be up-regulated in the serum of 32 BC patients compared to 22 healthy donors. Next, we performed Kaplan-Meier survival analysis for these 85 miRNAs and found that 10 miRNAs were positively correlated with metastases. To select the miRNAs specifically involved in BM, we compared the EVs derived miRNA profiles between bone metastatic cell lines and the parental cell lines (231BoM-1833 vs MDA-MB-231, MCF7-BoM2d vs MCF7). Among the 10 miRNAs, only miR-19a was significantly up-regulated in EVs derived from bone metastatic cell lines. MiR-19a was also found to be highly enriched in exosomes compared to microvesicles and apoptotic bodies. Lastly, we verified the high expression of miR-19a in the serum of BC-BM patients compared to the BC patients without BM. To study the role of miR19a in BC-BM, we applied the CRISPR/Cas9 technology to knockout the miR-19a in 231BoM-1833 and MCF7-BoM2d cells. The knockout of miR-19a didn’t alter the proliferation or migration of BC cells. However, it significantly decreased bone metastasis in our xenograft mouse models. We also found that the knockout of miR-19a decreased osteolytic lesions in the tumor-bearing bones, indicating the possible role of exosomal miR-19a in osteoclast cells. To test this hypothesis, we treated osteoclast cells with miR-19a-enriched exosomes and miR-19a-knockout exosomes. The results of tartrate-resistant acid phosphatase assay and bone resorption assay indicated that miR19a-enriched exosomes significantly promoted osteoclast differentiation and activity. Our study identified exosome derived miR-19a as a mediator of cell-cell communication between breast cancer and osteoclast cell, warranting further investigation on exosomal miR-19a as a novel biomarker and a therapeutic target for breast cancer bone metastasis. Citation Format: Kerui Wu, Jiamei Feng, Fei Xing, Yin Liu, Sambad Sharma, Kounosuke Watabe. Exosomal miR-19a: a novel communicator between cancer cell and osteoclast in osteolytic bone metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4940. doi:10.1158/1538-7445.AM2017-4940
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