Tumor Suppressor miRNA-204-5p Regulates Growth, Metastasis, and Immune Microenvironment Remodeling in Breast Cancer
Bok Sil Hong1, Han Suk Ryu2, Namshin Kim3,4
1Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
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.
Insights
MicroRNA-204-5p (miR-204-5p) acts as a tumor suppressor in breast cancer by inhibiting growth and metastasis. Its downregulation correlates with poor patient outcomes, and restoring miR-204-5p levels impacts cancer cell metabolism and the immune microenvironment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are crucial regulators in solid tumor development and progression.
- Dysregulation of specific miRNAs is implicated in various cancers, including breast cancer.
- Understanding the role of individual miRNAs is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the role of miR-204-5p in breast cancer growth, progression, and metastasis.
- To elucidate the molecular mechanisms underlying miR-204-5p's function in breast cancer.
- To explore the association between miR-204-5p expression and clinical outcomes in breast cancer patients.
Main Methods:
- Comparative analysis of miR-204-5p expression in breast cancer tissues versus normal tissues.
- In vitro studies involving overexpression of miR-204-5p in human and murine breast cancer cell lines.
- In vivo studies using mouse models to assess tumor growth and metastasis.
- Transcriptome and proteomic analyses to identify target pathways.
- Investigation of miR-204-5p's impact on the tumor immune microenvironment.
Main Results:
- miR-204-5p was significantly downregulated in breast cancer tissues and associated with poorer patient survival.
- Overexpression of miR-204-5p inhibited breast cancer cell viability, proliferation, migration, and altered cellular metabolism.
- miR-204-5p suppressed tumor growth and metastasis in vivo, targeting the PI3K/Akt pathway via PIK3CB.
- miR-204-5p modulated the immune microenvironment by altering myeloid and lymphocyte populations.
- Expression levels of miR-204-5p showed a nonlinear association with clinical outcomes and cancer cell behavior.
Conclusions:
- miR-204-5p functions as a tumor suppressor in breast cancer, inhibiting progression and metastasis.
- The PI3K/Akt pathway, particularly PIK3CB, is a key target of miR-204-5p in breast cancer.
- miR-204-5p influences both cell-autonomous and non-cell-autonomous effects, including immune microenvironment reprogramming.
- Restoring miR-204-5p levels represents a potential therapeutic strategy for breast cancer treatment.
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