Journal
CANCER RESEARCH
Volume 79, Issue 7, Pages 1520-1534Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-0891
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2015R1C1A1A02036629, 2015R1D1A1A02061904]
- National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea [HA15C0011]
- Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI13C2148]
- SNUH Research Fund [04-2016-0880]
- National Research Foundation of Korea [2015R1D1A1A02061904, 2015R1C1A1A02036629] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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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