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An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis
Published on: August 14, 2016
microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11
Wei-Luo Cai1,2, Wen-Ding Huang1, Bo Li2
1Department of Musculoskeletal Tumor, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China.
Background:
Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.
Methods:
In situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.
Results:
Herein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.
Conclusions:
Thus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.
Insights
MicroRNA-124 (miR-124) is reduced in breast cancer bone metastases, inhibiting osteoclast formation. Restoring miR-124 suppresses metastasis, offering new therapeutic targets for bone metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Bone metastases are a significant complication in advanced breast cancer, leading to severe morbidity.
- MicroRNA (miRNA) dysregulation plays a crucial role in the development of breast cancer bone metastases.
- The specific role of microRNA-124 (miR-124) in breast cancer bone metastasis remains largely unexplored.
Purpose of the Study:
- To investigate the role and underlying molecular mechanisms of miR-124 in the context of breast cancer bone metastasis.
- To determine if miR-124 can serve as a prognostic marker or therapeutic target for breast cancer bone metastases.
Main Methods:
- In situ hybridization (ISH) to assess miR-124 expression in tumor tissues.
- In vivo studies using a ventricle injection model to evaluate miR-124's effect on bone metastasis.
- In vitro assays to examine miR-124's function in osteoclast progenitor cell differentiation.
- Dual-luciferase reporter assays to identify miR-124 targets, specifically Interleukin-11 (IL-11).
- Kaplan-Meier analysis to correlate miR-124/IL-11 expression with patient prognosis.
Main Results:
- miR-124 expression was significantly decreased in bone metastatic tissues of breast cancer patients.
- Lower miR-124 levels correlated with aggressive disease characteristics and poorer survival outcomes.
- Restoring miR-124 inhibited, while its inhibition promoted, breast cancer bone metastasis in vivo.
- miR-124 suppressed osteoclast progenitor cell survival and differentiation, with IL-11 identified as a key mediator.
- IL-11 levels were inversely correlated with miR-124, and elevated IL-11 predicted a poor prognosis.
Conclusions:
- The miR-124/IL-11 axis is a critical regulator of breast cancer bone metastasis.
- Dysregulated miR-124 and elevated IL-11 are associated with poor prognosis in breast cancer patients with bone metastases.
- Targeting the miR-124/IL-11 pathway presents a promising therapeutic strategy for preventing and treating breast cancer bone metastases.
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