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Cancer Res. 2019 Apr 1;79(7):1520-1534. doi: 10.1158/0008-5472.CAN-18-0891. Epub 2019 Feb 8.

Tumor Suppressor miRNA-204-5p Regulates Growth, Metastasis, and Immune Microenvironment Remodeling in Breast Cancer.

Hong BS1, Ryu HS2, Kim N3,4, Kim J1,5, Lee E1,5, Moon H1, Kim KH3,4, Jin MS6, Kwon NH7, Kim S7,8, Kim D5, Chung DH5, Jeong K9, Kim K9, Kim KY10, Lee HB11, Han W11,12, Yun J12, Kim JI12, Noh DY11,12, Moon HG13,11,12.

Author information

1
Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
2
Department of Pathology, Seoul National University Hospital, Seoul, South Korea.
3
Personalized Genomic Medicine Research Center, Division of Strategic Research Groups, Korea Research Institute of Bioscience and Biotechnology, Daejeon.
4
Department of Functional Genomics, Korea University of Science and Technology, Daejeon, South Korea.
5
Department of Pathology, Seoul National University School of Medicine, Seoul, South Korea.
6
Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, South Korea.
7
Medicinal Bioconvergence Research Center, Seoul National University, Suwon, South Korea.
8
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, South Korea.
9
Division of Clinical Bioinformatics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
10
Department of Neurology, Seoul National University College of Medicine, Seoul, South Korea.
11
Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.
12
Genomic Medicine Institute, Seoul National University Medical Research Center, Seoul, South Korea.
13
Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea. moonhg74@snu.ac.kr.

Abstract

Various miRNAs play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of patients with breast cancer showed a nonlinear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor-immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis. SIGNIFICANCE: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer.

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